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1
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Yi E, Go J, Yun SH, Lee SE, Kwak J, Kim SW, Kim HS. CEACAM1-engineered MSCs have a broad spectrum of immunomodulatory functions and therapeutic potential via cell-to-cell interaction. Biomaterials 2024; 311:122667. [PMID: 38878480 DOI: 10.1016/j.biomaterials.2024.122667] [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: 01/17/2024] [Revised: 05/22/2024] [Accepted: 06/12/2024] [Indexed: 08/06/2024]
Abstract
Mesenchymal stem cells (MSCs) have garnered attention for their regenerative and immunomodulatory capabilities in clinical trials for various diseases. However, the effectiveness of MSC-based therapies, especially for conditions like graft-versus-host disease (GvHD), remains uncertain. The cytokine interferon (IFN)-γ has been known to enhance the immunosuppressive properties of MSCs through cell-to-cell interactions and soluble factors. In this study, we observed that IFN-γ-treated MSCs upregulated the expression of carcinoembryonic antigen-related cell adhesion molecule 1 (CEACAM1), associated with immune evasion through the inhibition of natural killer (NK) cell cytotoxicity. To co-opt this immunomodulatory function, we generated MSCs overexpressing CEACAM1 and found that CEACAM1-engineered MSCs significantly reduced NK cell activation and cytotoxicity via cell-to-cell interaction, independent of NKG2D ligand regulation. Furthermore, CEACAM1-engineered MSCs effectively inhibited the proliferation and activation of T cells along with the inflammatory responses of monocytes. In a humanized GvHD mouse model, CEACAM1-MSCs, particularly CEACAM1-4S-MSCs, demonstrated therapeutic potential by improving survival and alleviating symptoms. These findings suggest that CEACAM1 expression on MSCs contributes to MSC-mediated regulation of immune responses and that CEACAM1-engineered MSC could have therapeutic potential in conditions involving immune dysregulation.
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Affiliation(s)
- Eunbi Yi
- Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Jinyoung Go
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - So Hyeon Yun
- Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Sang Eun Lee
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea
| | - Jihye Kwak
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, Republic of Korea
| | - Seong Who Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
| | - Hun Sik Kim
- Department of Microbiology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea; Stem Cell Immunomodulation Research Center (SCIRC), University of Ulsan College of Medicine, Seoul, 05505, Republic of Korea.
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2
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Zhang X, You W, Wang Y, Dejenie R, Wang C, Huang Y, Li J. Prospects of anti-GD2 immunotherapy for retinoblastoma. Front Immunol 2024; 15:1499700. [PMID: 39620227 PMCID: PMC11604707 DOI: 10.3389/fimmu.2024.1499700] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2024] [Accepted: 10/21/2024] [Indexed: 12/11/2024] Open
Abstract
Retinoblastoma is the most common type of eye tumor in infants and children. Current treatments for retinoblastoma include intravenous chemotherapy, intra-arterial chemotherapy, intravitreal chemotherapy, cryotherapy, radiotherapy, and surgery. However, these treatments come accompanied by adverse effects such as the toxic side effects of chemotherapeutic drugs, post-operative complications including blindness after surgery, or other complications caused by radiotherapy. Immunotherapy is more promising for its low toxicity on normal cells and effectively improves the quality of life of patients. Disialoganglioside (GD2), a sphingolipid expressed on the surface of retinoblastoma, is a potential therapeutic target for retinoblastoma. We summarized immunotherapeutic approaches for both preclinical studies and clinical trials of GD2. An anti-GD2 monoclonal antibody (Dinutuximab), which has been approved for the treatment of high-risk neuroblastomas, has shown promising efficacy in improving patients' prognosis. Additionally, chimeric antigen receptors (CAR)-T therapy, GD2 vaccines and nanoparticles are also potential therapeutics. Finally, we discuss the prospects and current limitations of these immunotherapeutic approaches for treating retinoblastoma, as well as how to address these problems.
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Affiliation(s)
- Xinlong Zhang
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Wulin You
- Department of Orthopedics, Wuxi Hospital Affiliated of Nanjing University of Chinese Medicine, Wuxi, China
- Medical Center, University of Chicago, Chicago, IL, United States
| | - Yuntao Wang
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Rebeka Dejenie
- Medical Center, University of Chicago, Chicago, IL, United States
- School of Medicine, University of California, Davis, Davis, CA, United States
| | - Chenhao Wang
- Department of Orthopedics, Wuxi Hospital Affiliated of Nanjing University of Chinese Medicine, Wuxi, China
| | - Yan Huang
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
| | - Jingjing Li
- Affiliated Hospital of Shandong Second Medical University,School of Clinical Medicine, Shandong Second Medical University, Weifang, Shandong, China
- Jinming Yu Academician Workstation of Oncology, Shandong Second Medical University, Shandong, China
- School of Clinical Medicine, Shandong Second Medical University, Weifang, China
- Medical Center, University of Chicago, Chicago, IL, United States
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3
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Philippova J, Shevchenko J, Sennikov S. GD2-targeting therapy: a comparative analysis of approaches and promising directions. Front Immunol 2024; 15:1371345. [PMID: 38558810 PMCID: PMC10979305 DOI: 10.3389/fimmu.2024.1371345] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Accepted: 02/26/2024] [Indexed: 04/04/2024] Open
Abstract
Disialoganglioside GD2 is a promising target for immunotherapy with expression primarily restricted to neuroectodermal and epithelial tumor cells. Although its role in the maintenance and repair of neural tissue is well-established, its functions during normal organism development remain understudied. Meanwhile, studies have shown that GD2 plays an important role in tumorigenesis. Its functions include proliferation, invasion, motility, and metastasis, and its high expression and ability to transform the tumor microenvironment may be associated with a malignant phenotype. Structurally, GD2 is a glycosphingolipid that is stably expressed on the surface of tumor cells, making it a suitable candidate for targeting by antibodies or chimeric antigen receptors. Based on mouse monoclonal antibodies, chimeric and humanized antibodies and their combinations with cytokines, toxins, drugs, radionuclides, nanoparticles as well as chimeric antigen receptor have been developed. Furthermore, vaccines and photoimmunotherapy are being used to treat GD2-positive tumors, and GD2 aptamers can be used for targeting. In the field of cell therapy, allogeneic immunocompetent cells are also being utilized to enhance GD2 therapy. Efforts are currently being made to optimize the chimeric antigen receptor by modifying its design or by transducing not only αβ T cells, but also γδ T cells, NK cells, NKT cells, and macrophages. In addition, immunotherapy can combine both diagnostic and therapeutic methods, allowing for early detection of disease and minimal residual disease. This review discusses each immunotherapy method and strategy, its advantages and disadvantages, and highlights future directions for GD2 therapy.
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Affiliation(s)
| | | | - Sergey Sennikov
- Laboratory of Molecular Immunology, Federal State Budgetary Scientific Institution Research Institute of Fundamental and Clinical Immunology, Novosibirsk, Russia
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4
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Bodden M, Häcker A, Röder J, Kiefer A, Zhang C, Bhatti A, Pfeifer Serrahima J, Ullrich E, Kühnel I, Wels WS. Co-Expression of an IL-15 Superagonist Facilitates Self-Enrichment of GD 2-Targeted CAR-NK Cells and Mediates Potent Cell Killing in the Absence of IL-2. Cancers (Basel) 2023; 15:4310. [PMID: 37686586 PMCID: PMC10486391 DOI: 10.3390/cancers15174310] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2023] [Revised: 08/10/2023] [Accepted: 08/26/2023] [Indexed: 09/10/2023] Open
Abstract
In contrast to T lymphocytes, natural killer (NK) cells do not require prior sensitization but are rapidly activated upon encountering virally infected or neoplastic cells. In addition, NK cells can be safely applied in an allogeneic setting, making them important effector cells for the development of off-the-shelf therapeutics for adoptive cancer immunotherapy. To further enhance their therapeutic potential, here, we engineered continuously expanding NK-92 cells as a clinically relevant model to express a humanized second-generation chimeric antigen receptor (CAR) with a composite CD28-CD3ζ signaling domain (hu14.18.28.z) that targets the disialoganglioside GD2, which is expressed at high levels by neuroblastoma cells and other tumors of neuroectodermal origin. In a separate approach, we fused an IL-15 superagonist (RD-IL15) to the GD2-CAR via a P2A processing site. Lentivirally transduced NK-92/hu14.18.28.z and NK-92/hu14.18.28.z_RD-IL15 cells both displayed high and stable CAR surface expression and specific cytotoxicity toward GD2-positive tumor cells. GD2-CAR NK cells carrying the RD-IL15 construct in addition expressed the IL-15 superagonist, resulting in self-enrichment and targeted cell killing in the absence of exogenous IL-2. Furthermore, co-culture with RD-IL15-secreting GD2-CAR NK cells markedly enhanced proliferation and cytotoxicity of bystander immune cells in a paracrine manner. Our results demonstrate that GD2-CAR NK cells co-expressing the IL-15 superagonist mediate potent direct and indirect antitumor effects, suggesting this strategy as a promising approach for the further development of functionally enhanced cellular therapeutics.
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Affiliation(s)
- Malena Bodden
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe University, 60590 Frankfurt, Germany
| | - Aline Häcker
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
| | - Jasmin Röder
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe University, 60590 Frankfurt, Germany
| | - Anne Kiefer
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
| | - Congcong Zhang
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
| | - Anita Bhatti
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
| | - Jordi Pfeifer Serrahima
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
| | - Evelyn Ullrich
- Frankfurt Cancer Institute, Goethe University, 60590 Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, a Partnership between DKFZ and University Hospital Frankfurt, 60590 Frankfurt, Germany
- Department of Pediatrics, Experimental Immunology and Cell Therapy, Goethe University, 60590 Frankfurt, Germany
| | - Ines Kühnel
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
| | - Winfried S. Wels
- Georg-Speyer-Haus, Institute for Tumor Biology and Experimental Therapy, 60596 Frankfurt, Germany
- Frankfurt Cancer Institute, Goethe University, 60590 Frankfurt, Germany
- German Cancer Consortium (DKTK), Partner Site Frankfurt/Mainz, a Partnership between DKFZ and University Hospital Frankfurt, 60590 Frankfurt, Germany
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5
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Use of Brain-Derived Stem/Progenitor Cells and Derived Extracellular Vesicles to Repair Damaged Neural Tissues: Lessons Learned from Connective Tissue Repair Regarding Variables Limiting Progress and Approaches to Overcome Limitations. Int J Mol Sci 2023; 24:ijms24043370. [PMID: 36834779 PMCID: PMC9958575 DOI: 10.3390/ijms24043370] [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: 12/28/2022] [Revised: 01/27/2023] [Accepted: 02/06/2023] [Indexed: 02/11/2023] Open
Abstract
Pluripotent neural stem or progenitor cells (NSC/NPC) have been reported in the brains of adult preclinical models for decades, as have mesenchymal stem/stromal cells (MSC) been reported in a variety of tissues from adults. Based on their in vitro capabilities, these cell types have been used extensively in attempts to repair/regenerate brain and connective tissues, respectively. In addition, MSC have also been used in attempts to repair compromised brain centres. However, success in treating chronic neural degenerative conditions such as Alzheimer's disease, Parkinson's disease, and others with NSC/NPC has been limited, as have the use of MSC in the treatment of chronic osteoarthritis, a condition affecting millions of individuals. However, connective tissues are likely less complex than neural tissues regarding cell organization and regulatory integration, but some insights have been gleaned from the studies regarding connective tissue healing with MSC that may inform studies attempting to initiate repair and regeneration of neural tissues compromised acutely or chronically by trauma or disease. This review will discuss the similarities and differences in the applications of NSC/NPC and MSC, where some lessons have been learned, and potential approaches that could be used going forward to enhance progress in the application of cellular therapy to facilitate repair and regeneration of complex structures in the brain. In particular, variables that may need to be controlled to enhance success are discussed, as are different approaches such as the use of extracellular vesicles from stem/progenitor cells that could be used to stimulate endogenous cells to repair the tissues rather than consider cell replacement as the primary option. Caveats to all these efforts relate to whether cellular repair initiatives will have long-term success if the initiators for neural diseases are not controlled, and whether such cellular initiatives will have long-term success in a subset of patients if the neural diseases are heterogeneous and have multiple etiologies.
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Santilli F, Fabrizi J, Pulcini F, Santacroce C, Sorice M, Delle Monache S, Mattei V. Gangliosides and Their Role in Multilineage Differentiation of Mesenchymal Stem Cells. Biomedicines 2022; 10:biomedicines10123112. [PMID: 36551867 PMCID: PMC9775755 DOI: 10.3390/biomedicines10123112] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/10/2022] [Accepted: 11/30/2022] [Indexed: 12/05/2022] Open
Abstract
Gangliosides (GGs) are a glycolipid class present on Mesenchymal Stem Cells (MSCs) surfaces with a critical appearance role in stem cell differentiation, even though their mechanistic role in signaling and differentiation remains largely unknown. This review aims to carry out a critical analysis of the predictive role of gangliosides as specific markers of the cellular state of undifferentiated and differentiated MSCs, towards the osteogenic, chondrogenic, neurogenic, and adipogenic lineage. For this reason, we analyzed the role of GGs during multilineage differentiation processes of several types of MSCs such as Umbilical Cord-derived MSCs (UC-MSCs), Bone Marrow-derived MSCs (BM-MSCs), Dental Pulp derived MSCs (DPSCs), and Adipose derived MSCs (ADSCs). Moreover, we examined the possible role of GGs as specific cell surface markers to identify or isolate specific stem cell isotypes and their potential use as additional markers for quality control of cell-based therapies.
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Affiliation(s)
- Francesca Santilli
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, Angelo Maria Ricci 35A, 02100 Rieti, Italy
| | - Jessica Fabrizi
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, Angelo Maria Ricci 35A, 02100 Rieti, Italy
- Department of Experimental Medicine, Sapienza University, Regina Elena 324, 00161 Rome, Italy
| | - Fanny Pulcini
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Vetoio, 67100 L’Aquila, Italy
| | - Costantino Santacroce
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, Angelo Maria Ricci 35A, 02100 Rieti, Italy
| | - Maurizio Sorice
- Department of Experimental Medicine, Sapienza University, Regina Elena 324, 00161 Rome, Italy
| | - Simona Delle Monache
- Department of Biotechnological and Applied Clinical Sciences, University of L’Aquila, Vetoio, 67100 L’Aquila, Italy
- Correspondence: (S.D.M.); (V.M.)
| | - Vincenzo Mattei
- Biomedicine and Advanced Technologies Rieti Center, Sabina Universitas, Angelo Maria Ricci 35A, 02100 Rieti, Italy
- Correspondence: (S.D.M.); (V.M.)
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7
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Hohenwallner K, Troppmair N, Panzenboeck L, Kasper C, El Abiead Y, Koellensperger G, Lamp LM, Hartler J, Egger D, Rampler E. Decoding Distinct Ganglioside Patterns of Native and Differentiated Mesenchymal Stem Cells by a Novel Glycolipidomics Profiling Strategy. JACS AU 2022; 2:2466-2480. [PMID: 36465531 PMCID: PMC9709940 DOI: 10.1021/jacsau.2c00230] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 10/01/2022] [Accepted: 10/03/2022] [Indexed: 06/17/2023]
Abstract
Gangliosides are an indispensable glycolipid class concentrated on cell surfaces with a critical role in stem cell differentiation. Nonetheless, owing to the lack of suitable methods for scalable analysis covering the full scope of ganglioside molecular diversity, their mechanistic properties in signaling and differentiation remain undiscovered to a large extent. This work introduces a sensitive and comprehensive ganglioside assay based on liquid chromatography, high-resolution mass spectrometry, and multistage fragmentation. Complemented by an open-source data evaluation workflow, we provide automated in-depth lipid species-level and molecular species-level annotation based on decision rule sets for all major ganglioside classes. Compared to conventional state-of-the-art methods, the presented ganglioside assay offers (1) increased sensitivity, (2) superior structural elucidation, and (3) the possibility to detect novel ganglioside species. A major reason for the highly improved sensitivity is the optimized spectral readout based on the unique capability of two parallelizable mass analyzers for multistage fragmentation. We demonstrated the high-throughput universal capability of our novel analytical strategy by identifying 254 ganglioside species. As a proof of concept, 137 unique gangliosides were annotated in native and differentiated human mesenchymal stem cells including 78 potential cell-state-specific markers and 38 previously unreported gangliosides. A general increase of the ganglioside numbers upon differentiation was observed as well as cell-state-specific clustering based on the ganglioside species patterns. The combination of the developed glycolipidomics assay with the extended automated annotation tool enables comprehensive in-depth ganglioside characterization as shown on biological samples of interest. Our results suggest ganglioside patterns as a promising quality control tool for stem cells and their differentiation products. Additionally, we believe that our analytical workflow paves the way for probing glycolipid-based biochemical processes shedding light on the enigmatic processes of gangliosides and glycolipids in general.
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Affiliation(s)
- Katharina Hohenwallner
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
- Vienna
Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna 1090, Austria
| | - Nina Troppmair
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
- Vienna
Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna 1090, Austria
| | - Lisa Panzenboeck
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
- Vienna
Doctoral School in Chemistry (DoSChem), University of Vienna, Vienna 1090, Austria
| | - Cornelia Kasper
- Institute
of Cell and Tissue Culture Technologies, University of Natural Resources and Life Sciences, Vienna 1190, Austria
| | - Yasin El Abiead
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Gunda Koellensperger
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
| | - Leonida M. Lamp
- Institute
of Pharmaceutical Sciences, University of
Graz, Graz 8010, Austria
| | - Jürgen Hartler
- Institute
of Pharmaceutical Sciences, University of
Graz, Graz 8010, Austria
- Field
of Excellence BioHealth − University
of Graz, Graz 8010, Austria
| | - Dominik Egger
- Institute
of Cell and Tissue Culture Technologies, University of Natural Resources and Life Sciences, Vienna 1190, Austria
| | - Evelyn Rampler
- Department
of Analytical Chemistry, Faculty of Chemistry, University of Vienna, Vienna 1090, Austria
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Kim M, Go J, Kwon JH, Jin HJ, Bae YK, Kim EY, Chang EJ, Choi SJ, Kim SW. CD26 Inhibition Potentiates the Therapeutic Effects of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells by Delaying Cellular Senescence. Front Cell Dev Biol 2022; 9:803645. [PMID: 35178399 PMCID: PMC8846329 DOI: 10.3389/fcell.2021.803645] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2021] [Accepted: 12/23/2021] [Indexed: 12/27/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are recognized as potential treatments for multiple degenerative and inflammatory disorders as a number of animal and human studies have indicated their therapeutic effects. There are also several clinically approved medicinal products that are manufactured using these cells. For such large-scale manufacturing requirements, the in vitro expansion of harvested MSCs is essential. Multiple subculturing of MSCs, however, provokes cellular senescence processes which is known to deteriorate the therapeutic efficacy of the cells. Strategies to rejuvenate or selectively remove senescent MSCs are therefore highly desirable for fostering future clinical applications of these cells. In this present study, we investigated gene expression changes related to cellular senescence of MSCs derived from umbilical cord blood and found that CD26, also known as DPP4, is significantly upregulated upon cellular aging. We further observed that the inhibition of CD26 by genetic or pharmacologic means delayed the cellular aging of MSCs with their multiple passaging in culture. Moreover, the sorting and exclusion of CD26-positive MSCs from heterogenous cell population enhanced in vitro cell attachment and reduced senescence-associated cytokine secretion. CD26-negative MSCs also showed superior therapeutic efficacy in mouse lung emphysema model. Our present results collectively suggest CD26 is a potential novel target for the rejuvenation of senescent MSCs for their use in manufacturing MSC-based applications.
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Affiliation(s)
- Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Jinyoung Go
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Ji Hye Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Eun-Young Kim
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Eun-Ju Chang
- Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam, South Korea
| | - Seong Who Kim
- Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea
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9
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Fu J, Wang Y, Jiang Y, Du J, Xu J, Liu Y. Systemic therapy of MSCs in bone regeneration: a systematic review and meta-analysis. Stem Cell Res Ther 2021; 12:377. [PMID: 34215342 PMCID: PMC8254211 DOI: 10.1186/s13287-021-02456-w] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Accepted: 06/12/2021] [Indexed: 12/30/2022] Open
Abstract
Objectives Over the past decades, many studies focused on mesenchymal stem cells (MSCs) therapy for bone regeneration. Due to the efficiency of topical application has been widely dicussed and systemic application was also a feasible way for new bone formation, the aim of this study was to systematically review systemic therapy of MSCs for bone regeneration in pre-clinical studies. Methods The article search was conducted in PubMed and Embase databases. Original research articles that assessed potential effect of systemic application of MSCs for bone regeneration in vivo were selected and evaluated in this review, according to eligibility criteria. The efficacy of MSC systemic treatment was analyzed by random effects meta-analysis, and the outcomes were expressed in standard mean difference (SMD) and its 95% confidence interval. Subgroup analyses were conducted on animal species and gender, MSCs types, frequency and time of injection, and bone diseases. Results Twenty-three articles were selected in this review, of which 21 were included in meta-analysis. The results showed that systemic therapy increased bone mineral density (SMD 3.02 [1.84, 4.20]), bone volume to tissue volume ratio (2.10 [1.16, 3.03]), and the percentage of new bone area (7.03 [2.10, 11.96]). Bone loss caused by systemic disease tended to produce a better response to systemic treatment (p=0.05 in BMD, p=0.03 in BV/TV). Conclusion This study concluded that systemic therapy of MSCs promotes bone regeneration in preclinical experiments. These results provided important information for the systemic application of MSCs as a potential application of bone formation in further animal experiments. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-021-02456-w.
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Affiliation(s)
- Jingfei Fu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yanxue Wang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Yiyang Jiang
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Juan Du
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China
| | - Junji Xu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
| | - Yi Liu
- Laboratory of Tissue Regeneration and Immunology and Department of Periodontics, Beijing Key Laboratory of Tooth Regeneration and Function Reconstruction, School of Stomatology, Capital Medical University, Tian Tan Xi Li No.4, Beijing, 100050, People's Republic of China.
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10
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Furman WL. Monoclonal Antibody Therapies for High Risk Neuroblastoma. Biologics 2021; 15:205-219. [PMID: 34135571 PMCID: PMC8200163 DOI: 10.2147/btt.s267278] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2021] [Accepted: 05/10/2021] [Indexed: 01/13/2023]
Abstract
Monoclonal antibodies (mAbs) are part of the standard of care for the treatment of many adult solid tumors. Until recently none have been approved for use in children with solid tumors. Neuroblastoma (NB) is the most common extracranial solid tumor in children. Those with high-risk disease, despite treatment with very intensive multimodal therapy, still have poor overall survival. Results of treatment with an immunotherapy regimen using a chimeric (human/mouse) mAb against a cell surface disialoganglioside (GD2) have changed the standard of care for these children and resulted in the first approval of a mAb for use in children with solid tumors. This article will review the use of the various anti-GD2 mAbs in children with NB, methods that have been or are being evaluated for enhancing their efficacy, as well as review other promising antigenic targets for the therapeutic use of mAbs in children with NB.
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Affiliation(s)
- Wayne L Furman
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN, USA
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11
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Um S, Ha J, Choi SJ, Oh W, Jin HJ. Prospects for the therapeutic development of umbilical cord blood-derived mesenchymal stem cells. World J Stem Cells 2020; 12:1511-1528. [PMID: 33505598 PMCID: PMC7789129 DOI: 10.4252/wjsc.v12.i12.1511] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Revised: 10/23/2020] [Accepted: 11/12/2020] [Indexed: 02/06/2023] Open
Abstract
Umbilical cord blood (UCB) is a primitive and abundant source of mesenchymal stem cells (MSCs). UCB-derived MSCs have a broad and efficient therapeutic capacity to treat various diseases and disorders. Despite the high latent self-renewal and differentiation capacity of these cells, the safety, efficacy, and yield of MSCs expanded for ex vivo clinical applications remains a concern. However, immunomodulatory effects have emerged in various disease models, exhibiting specific mechanisms of action, such as cell migration and homing, angiogenesis, anti-apoptosis, proliferation, anti-cancer, anti-fibrosis, anti-inflammation and tissue regeneration. Herein, we review the current literature pertaining to the UCB-derived MSC application as potential treatment strategies, and discuss the concerns regarding the safety and mass production issues in future applications.
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Affiliation(s)
- Soyoun Um
- Research Team for Immune Cell Therapy, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Jueun Ha
- Research Team for Osteoarthritis, Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seongnam 13494, South Korea
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12
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Yu J, Hung JT, Wang SH, Cheng JY, Yu AL. Targeting glycosphingolipids for cancer immunotherapy. FEBS Lett 2020; 594:3602-3618. [PMID: 32860713 DOI: 10.1002/1873-3468.13917] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 08/20/2020] [Accepted: 08/20/2020] [Indexed: 11/07/2022]
Abstract
Aberrant expression of glycosphingolipids (GSLs) is a unique feature of cancer and stromal cells in tumor microenvironments. Although the impact of GSLs on tumor progression remains largely unclear, anticancer immunotherapies directed against GSLs are attracting growing attention. Here, we focus on GD2, a disialoganglioside expressed in tumors of neuroectodermal origin, and Globo H ceramide (GHCer), the most prevalent cancer-associated GSL overexpressed in a variety of epithelial cancers. We first summarize recent advances on our understanding of GD2 and GHCer biology and then discuss the clinical development of the first immunotherapeutic agent targeting a glycolipid, the GD2-specific antibody dinutuximab, its approved indications, and new strategies to improve its efficacy for neuroblastoma. Next, we review ongoing clinical trials on Globo H-targeted immunotherapeutics. We end with highlighting how these studies provide sound scientific rationales for targeting GSLs in cancer and may facilitate a rational design of new GSL-targeted anticancer therapeutics.
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Affiliation(s)
- John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.,Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Sheng-Hung Wang
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Jing-Yan Cheng
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Alice L Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan.,Department of Pediatrics, University of California in San Diego, La Jolla, CA, USA
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13
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Kailayangiri S, Altvater B, Lesch S, Balbach S, Göttlich C, Kühnemundt J, Mikesch JH, Schelhaas S, Jamitzky S, Meltzer J, Farwick N, Greune L, Fluegge M, Kerl K, Lode HN, Siebert N, Müller I, Walles H, Hartmann W, Rossig C. EZH2 Inhibition in Ewing Sarcoma Upregulates G D2 Expression for Targeting with Gene-Modified T Cells. Mol Ther 2019; 27:933-946. [PMID: 30879952 DOI: 10.1016/j.ymthe.2019.02.014] [Citation(s) in RCA: 69] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2019] [Revised: 02/15/2019] [Accepted: 02/15/2019] [Indexed: 12/21/2022] Open
Abstract
Chimeric antigen receptor (CAR) engineering of T cells allows one to specifically target tumor cells via cell surface antigens. A candidate target in Ewing sarcoma is the ganglioside GD2, but heterogeneic expression limits its value. Here we report that pharmacological inhibition of Enhancer of Zeste Homolog 2 (EZH2) at doses reducing H3K27 trimethylation, but not cell viability, selectively and reversibly induces GD2 surface expression in Ewing sarcoma cells. EZH2 in Ewing sarcoma cells directly binds to the promoter regions of genes encoding for two key enzymes of GD2 biosynthesis, and EZH2 inhibition enhances expression of these genes. GD2 surface expression in Ewing sarcoma cells is not associated with distinct in vitro proliferation, colony formation, chemosensitivity, or in vivo tumorigenicity. Moreover, disruption of GD2 synthesis by gene editing does not affect its in vitro behavior. EZH2 inhibitor treatment sensitizes Ewing sarcoma cells to effective cytolysis by GD2-specific CAR gene-modified T cells. In conclusion, we report a clinically applicable pharmacological approach for enhancing efficacy of adoptively transferred GD2-redirected T cells against Ewing sarcoma, by enabling recognition of tumor cells with low or negative target expression.
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Affiliation(s)
- Sareetha Kailayangiri
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Bianca Altvater
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Stefanie Lesch
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany; Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80539 Munich, Germany
| | - Sebastian Balbach
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Claudia Göttlich
- Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070 Würzburg, Germany; Fraunhofer Institute for Silicate Research (ISC), Translational Center Regenerative Therapies, 97082 Würzburg, Germany
| | - Johanna Kühnemundt
- Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070 Würzburg, Germany; Fraunhofer Institute for Silicate Research (ISC), Translational Center Regenerative Therapies, 97082 Würzburg, Germany
| | - Jan-Henrik Mikesch
- Department of Medicine A, University Hospital Münster, 48149 Münster, Germany
| | - Sonja Schelhaas
- European Institute for Molecular Imaging (EIMI), University of Münster, 48149 Münster, Germany
| | - Silke Jamitzky
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Jutta Meltzer
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Nicole Farwick
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Lea Greune
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Maike Fluegge
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Kornelius Kerl
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany
| | - Holger N Lode
- Pediatric Hematology and Oncology, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Nikolai Siebert
- Pediatric Hematology and Oncology, University Medicine Greifswald, 17475 Greifswald, Germany
| | - Ingo Müller
- Division of Pediatric Stem Cell Transplantation and Immunology, Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany
| | - Heike Walles
- Tissue Engineering and Regenerative Medicine, University Hospital Würzburg, 97070 Würzburg, Germany; Fraunhofer Institute for Silicate Research (ISC), Translational Center Regenerative Therapies, 97082 Würzburg, Germany
| | - Wolfgang Hartmann
- Division of Translational Pathology, Gerhard-Domagk Institute for Pathology, University of Münster, 48149 Münster, Germany
| | - Claudia Rossig
- Department of Pediatric Hematology and Oncology, University Children's Hospital Münster, 48149 Münster, Germany; Cells-in-Motion Cluster of Excellence (EXC 1003 - CiM), University of Münster, 48149 Münster, Germany.
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14
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The role of interleukin-2, all-trans retinoic acid, and natural killer cells: surveillance mechanisms in anti-GD2 antibody therapy in neuroblastoma. Cancer Immunol Immunother 2018; 67:615-626. [PMID: 29327110 DOI: 10.1007/s00262-017-2108-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2017] [Accepted: 12/14/2017] [Indexed: 02/05/2023]
Abstract
Although anti-disialoganglioside (GD2) antibodies are successfully used for neuroblastoma therapy, a third of patients with neuroblastoma experience treatment failure or serious toxicity. Various strategies have been employed in the clinic to improve antibody-dependent cell-mediated cytotoxicity (ADCC), such as the addition of interleukin (IL)-2 to enhance natural killer (NK) cell function, adoptive transfer of allogeneic NK cells to exploit immune surveillance, and retinoid-induced differentiation therapy. Nevertheless, these mechanisms are not fully understood. We developed a quantitative assay to test ADCC induced by the anti-GD2 antibody Hu14.18K322A in nine neuroblastoma cell lines and dissociated cells from orthotopic patient-derived xenografts (O-PDXs) in culture. IL-2 improved ADCC against neuroblastoma cells, and differentiation with all-trans retinoic acid stabilized GD2 expression on tumor cells and enhanced ADCC as well. Degranulation was highest in licensed NK cells that expressed CD158b (P < 0.001) and harbored a killer-cell immunoglobulin-like receptor (KIR) mismatch against the tumor-specific human leukocyte antigen (HLA; P = 0.016). In conclusion, IL-2 is an important component of immunotherapy because it can improve the cytolytic function of NK cells against neuroblastoma cells and could lower the antibody dose required for efficacy, thereby reducing toxicity. The effect of IL-2 may vary among individuals and a biomarker would be useful to predict ADCC following IL-2 activation. Sub-populations of NK cells may have different levels of activity dependent on their licensing status, KIR expression, and HLA-KIR interaction. Better understanding of HLA-KIR interactions and the molecular changes following retinoid-induced differentiation is necessary to delineate their role in ADCC.
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15
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Park JH, Jang HR, Kim DH, Kwon GY, Lee JE, Huh W, Choi SJ, Oh W, Oh HY, Kim YG. Early, but not late, treatment with human umbilical cord blood-derived mesenchymal stem cells attenuates cisplatin nephrotoxicity through immunomodulation. Am J Physiol Renal Physiol 2017; 313:F984-F996. [PMID: 28356286 DOI: 10.1152/ajprenal.00097.2016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/16/2016] [Revised: 03/13/2017] [Accepted: 03/23/2017] [Indexed: 11/22/2022] Open
Abstract
Preemptive treatment with mesenchymal stem cells (MSCs) can attenuate cisplatin-induced acute kidney injury (AKI). However, it is uncertain whether MSC treatment after the development of renal dysfunction prevents AKI progression or if MSC immunomodulatory properties contribute to MSC therapy. In this study, human umbilical cord blood (hUCB)-derived MSCs were used to compare the effects and mechanisms of early and late MSC therapy in a murine model. After cisplatin injection into C57BL/6 mice, hUCB-MSCs were administered on day 1 (early treatment) or day 3 (late treatment). With early treatment, cisplatin nephrotoxicity was attenuated as evidenced by decreased blood urea nitrogen (BUN) and reduced apoptosis and tubular injury scores on day 3 Early treatment resulted in downregulation of intrarenal monocyte chemotactic protein-1 and IL-6 expression and upregulation of IL-10 and VEGF expression. Flow cytometric analysis showed similar populations of infiltrated immune cells in both groups; however, regulatory T-cell (Treg) infiltration was 2.5-fold higher in the early treatment group. The role of Tregs was confirmed by the blunted effect of early treatment on renal injury after Treg depletion. In contrast, late treatment (at a time when BUN levels were 2-fold higher than baseline levels) showed no renoprotective effects on day 6 Neither the populations of intrarenal infiltrating immune cells (including Tregs) nor cytokine expression levels were affected by late treatment. Our results suggest that early MSC treatment attenuates renal injury by Treg induction and immunomodulation, whereas a late treatment (i.e., after the development of renal dysfunction) does not prevent AKI progression or alter the intrarenal inflammatory micromilieu.
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Affiliation(s)
- Ji Hyeon Park
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Medicine, National Police Hospital, Seoul, Korea; and
| | - Hye Ryoun Jang
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Do Hee Kim
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.,Department of Internal Medicine, Chungbuk National University Hospital, Cheongju, Korea
| | - Ghee Young Kwon
- Department of Pathology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Jung Eun Lee
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wooseong Huh
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Soo Jin Choi
- Biomedical Research Institute, R&D Center, Medipost Company, Gyeonggi-do, Korea
| | - Wonil Oh
- Biomedical Research Institute, R&D Center, Medipost Company, Gyeonggi-do, Korea
| | - Ha Young Oh
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon-Goo Kim
- Division of Nephrology, Department of Medicine, Stem Cell and Regenerative Medicine Institute, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea;
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16
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Park HW, Kim Y, Chang JW, Yang YS, Oh W, Lee JM, Park HR, Kim DG, Paek SH. Effect of Single and Double Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells Following Focal Cerebral Ischemia in Rats. Exp Neurobiol 2017; 26:55-65. [PMID: 28243167 PMCID: PMC5326715 DOI: 10.5607/en.2017.26.1.55] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 02/09/2017] [Accepted: 02/13/2017] [Indexed: 01/01/2023] Open
Abstract
Stem cell therapies are administered during the acute phase of stroke to preserve the penumbral tissues from ischemic injury. However, the effect of repeated cell therapy during the acute phase remains unclear. In this study, we investigated and compared the functional outcome of single (two days post-injury) and repeated (two and nine days post-injury) treatment with human umbilical cord derived mesenchymal stem cells (hUCB-MSCs) after middle cerebral artery occlusion (MCAO). The rotarod and limb placement tests were utilized to investigate functional outcomes, while infarct volume and tissue damage were measured by immunofluorescent staining for neovascularization, neurogenesis, apoptosis, and inflammation in the penumbral zones. We observed notable motor dysfunction and a significant decrease in infarcted brain volume, as well as increases in neurons and vessels in both single and repeated hUCB-MSC treatments compared to the control group. Interestingly, repeated administration of hUCB-MSCs was not found to elicit additional or synergistic improvements over monotherapy. This study suggests that a clearer understanding of the therapeutic window after stroke will facilitate the development of more efficient treatment protocols in the clinical application of stem cell therapy.
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Affiliation(s)
- Hyung Woo Park
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea.; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Yona Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea.; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Jong Wook Chang
- Stem Cell & Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
| | - Yoon Sun Yang
- Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 13494, Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 13494, Korea
| | - Jae Min Lee
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hye Ran Park
- Department of Neurosurgery, Soonchunhyang University Hospital, Seoul 31151, Korea
| | - Dong Gyu Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea.; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Sun Ha Paek
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03080, Korea.; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03080, Korea.; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03080, Korea
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17
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Yu AL, Hung JT, Ho MY, Yu J. Alterations of Glycosphingolipids in Embryonic Stem Cell Differentiation and Development of Glycan-Targeting Cancer Immunotherapy. Stem Cells Dev 2016; 25:1532-1548. [DOI: 10.1089/scd.2016.0138] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Affiliation(s)
- Alice L. Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
- Genomics Research Center, Academia Sinica, Taipei, Taiwan
| | - Jung-Tung Hung
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - Ming-Yi Ho
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
| | - John Yu
- Institute of Stem Cell and Translational Cancer Research, Chang Gung Memorial Hospital at Linkou, Chang Gung University, Taoyuan, Taiwan
- Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan
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18
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Jin HJ, Lee HJ, Heo J, Lim J, Kim M, Kim MK, Nam HY, Hong GH, Cho YS, Choi SJ, Kim IG, Shin DM, Kim SW. Senescence-Associated MCP-1 Secretion Is Dependent on a Decline in BMI1 in Human Mesenchymal Stromal Cells. Antioxid Redox Signal 2016; 24:471-85. [PMID: 26573462 PMCID: PMC4800271 DOI: 10.1089/ars.2015.6359] [Citation(s) in RCA: 72] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
AIMS Cellular senescence and its secretory phenotype (senescence-associated secretory phenotype [SASP]) develop after long-term expansion of mesenchymal stromal cells (MSCs). Further investigation of this phenotype is required to improve the therapeutic efficacy of MSC-based cell therapies. In this study, we show that positive feedback between SASP and inherent senescence processes plays a crucial role in the senescence of umbilical cord blood-derived MSCs (UCB-MSCs). RESULTS We found that monocyte chemoattractant protein-1 (MCP-1) was secreted as a dominant component of the SASP during expansion of UCB-MSCs and reinforced senescence via its cognate receptor chemokine (c-c motif) receptor 2 (CCR2) by activating the ROS-p38-MAPK-p53/p21 signaling cascade in both an autocrine and paracrine manner. The activated p53 in turn increased MCP-1 secretion, completing a feed-forward loop that triggered the senescence program in UCB-MSCs. Accordingly, knockdown of CCR2 in UCB-MSCs significantly improved their therapeutic ability to alleviate airway inflammation in an experimental allergic asthma model. Moreover, BMI1, a polycomb protein, repressed the expression of MCP-1 by binding to its regulatory elements. The reduction in BMI1 levels during UCB-MSC senescence altered the epigenetic status of MCP-1, including the loss of H2AK119Ub, and resulted in derepression of MCP-1. INNOVATION Our results provide the first evidence supporting the existence of the SASP as a causative contributor to UCB-MSC senescence and reveal a so far unappreciated link between epigenetic regulation and SASP for maintaining a stable senescent phenotype. CONCLUSION Senescence of UCB-MSCs is orchestrated by MCP-1, which is secreted as a major component of the SASP and is epigenetically regulated by BMI1.
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Affiliation(s)
- Hye Jin Jin
- 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea
| | - Hyang Ju Lee
- 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jinbeom Heo
- 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Jisun Lim
- 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul, Korea
| | - Miyeon Kim
- 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea
| | - Min Kyung Kim
- 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Hae Yun Nam
- 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Gyong Hwa Hong
- 6 Graduate School of Medical Science and Engineering, Biomedical Research Center, KAIST Institute for the BioCentury, Korea Advanced Institute of Science and Technology , Daejeon, Korea
| | - You Sook Cho
- 7 Division of Allergy and Clinical Immunology, Department of Internal Medicine, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Soo Jin Choi
- 2 Biomedical Research Institute , MEDIPOST Co., Ltd., Seongnam, Korea
| | - In-Gyu Kim
- 5 Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine , Seoul, Korea
| | - Dong-Myung Shin
- 3 Department of Biomedical Sciences, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea.,4 Department of Physiology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
| | - Seong Who Kim
- 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
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19
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Jin HJ, Kwon JH, Kim M, Bae YK, Choi SJ, Oh W, Yang YS, Jeon HB. Downregulation of Melanoma Cell Adhesion Molecule (MCAM/CD146) Accelerates Cellular Senescence in Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells. Stem Cells Transl Med 2016; 5:427-39. [PMID: 26941359 DOI: 10.5966/sctm.2015-0109] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2015] [Accepted: 11/06/2015] [Indexed: 12/22/2022] Open
Abstract
UNLABELLED Therapeutic applications of mesenchymal stem cells (MSCs) for treating various diseases have increased in recent years. To ensure that treatment is effective, an adequate MSC dosage should be determined before these cells are used for therapeutic purposes. To obtain a sufficient number of cells for therapeutic applications, MSCs must be expanded in long-term cell culture, which inevitably triggers cellular senescence. In this study, we investigated the surface markers of human umbilical cord blood-derived MSCs (hUCB-MSCs) associated with cellular senescence using fluorescence-activated cell sorting analysis and 242 cell surface-marker antibodies. Among these surface proteins, we selected the melanoma cell adhesion molecule (MCAM/CD146) for further study with the aim of validating observed expression differences and investigating the associated implications in hUCB-MSCs during cellular senescence. We observed that CD146 expression markedly decreased in hUCB-MSCs following prolonged in vitro expansion. Using preparative sorting, we found that hUCB-MSCs with high CD146 expression displayed high growth rates, multilineage differentiation, expression of stemness markers, and telomerase activity, as well as significantly lower expression of the senescence markers p16, p21, p53, and senescence-associated β-galactosidase, compared with that observed in hUCB-MSCs with low-level CD146 expression. In contrast, CD146 downregulation with small interfering RNAs enhanced the senescence phenotype. In addition, CD146 suppression in hUCB-MSCs caused downregulation of other cellular senescence regulators, including Bmi-1, Id1, and Twist1. Collectively, our results suggest that CD146 regulates cellular senescence; thus, it could be used as a therapeutic marker to identify senescent hUCB-MSCs. SIGNIFICANCE One of the fundamental requirements for mesenchymal stem cell (MSC)-based therapies is the expansion of MSCs during long-term culture because a sufficient number of functional cells is required. However, long-term growth inevitably induces cellular senescence, which potentially causes poor clinical outcomes by inducing growth arrest and the loss of stem cell properties. Thus, the identification of markers for evaluating the status of MSC senescence during long-term culture may enhance the success of MSC-based therapy. This study provides strong evidence that CD146 is a novel and useful marker for predicting senescence in human umbilical cord blood-derived MSCs (hUCB-MSCs), and CD146 can potentially be applied in quality-control assessments of hUCB-MSC-based therapy.
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Affiliation(s)
- Hye Jin Jin
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Ji Hye Kwon
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Miyeon Kim
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Yun Kyung Bae
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Soo Jin Choi
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Wonil Oh
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Yoon Sun Yang
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
| | - Hong Bae Jeon
- Biomedical Research Institute, R&D Center, MEDIPOST Co., Ltd., Gyeonggi-do, Republic of Korea
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20
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Park HW, Chang JW, Yang YS, Oh W, Hwang JH, Kim DG, Paek SH. The Effect of Donor-Dependent Administration of Human Umbilical Cord Blood-Derived Mesenchymal Stem Cells following Focal Cerebral Ischemia in Rats. Exp Neurobiol 2015; 24:358-65. [PMID: 26713083 PMCID: PMC4688335 DOI: 10.5607/en.2015.24.4.358] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2015] [Revised: 10/27/2015] [Accepted: 10/29/2015] [Indexed: 01/02/2023] Open
Abstract
Stroke is an ischemic disease caused by clotted vessel-induced cell damage. It is characterized by high morbidity and mortality and is typically treated with a tissue plasminogen activator (tPA). However, this therapy is limited by temporal constraints. Recently, several studies have focused on cell therapy as an alternative treatment. Most researches have used fixed donor cell administration, and hence, the effect of donor-dependent cell administration is unknown. In this study, we administered 3 types of donor-derived human umbilical cord blood mesenchymal stem cells (hUCB-MSCs) in the ischemic boundary zone of the ischemic stroke rat model. We then performed functional and pathological characterization using rotarod, the limb placement test, and immunofluorescent staining. We observed a significant decrease in neuron number, and notable stroke-like motor dysfunction, as assessed by the rotarod test (~40% decrease in time) and the limb placement test (4.5 point increase) in control rats with ischemic stroke. The neurobehavioral performance of the rats with ischemic stroke that were treated with hUCB-MSCs was significantly better than that of rats in the vehicle-injected control group. Regardless of which donor cells were used, hUCB-MSC transplantation resulted in an accumulation of neuronal progenitor cells, and angiogenic and tissue repair factors in the ischemic boundary zone. The neurogenic and angiogenic profiles of the 3 types of hUCB-MSCs were very similar. Our results suggest that intraparenchymal administration of hUCB-MSCs results in significant therapeutic effects in the ischemic brain regardless of the type of donor.
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Affiliation(s)
- Hyung Woo Park
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03082, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03082, Korea
| | - Jong Wook Chang
- Stem Cell & Regenerative Medicine Center, Research Institute for Future Medicine, Samsung Medical Center, Seoul 06351, Korea
| | - Yoon Sun Yang
- Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 13494, Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd, Seoul 13494, Korea
| | - Jae Ha Hwang
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03082, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03082, Korea
| | - Dong Gyu Kim
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03082, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03082, Korea
| | - Sun Ha Paek
- Department of Neurosurgery, Seoul National University College of Medicine, Seoul 03082, Korea. ; Cancer Research Institute, Seoul National University College of Medicine, Seoul 03082, Korea. ; Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Seoul 03082, Korea
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21
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Shao J, Zhang W, Yang T. Using mesenchymal stem cells as a therapy for bone regeneration and repairing. Biol Res 2015; 48:62. [PMID: 26530042 PMCID: PMC4630918 DOI: 10.1186/s40659-015-0053-4] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Accepted: 10/22/2015] [Indexed: 02/07/2023] Open
Abstract
Bone is a unique tissue which could regenerate completely after injury rather than heal itself with a scar. Compared with other tissues the difference is that, during bone repairing and regeneration, after the inflammatory phase the mesenchymal stem cells (MSCs) are recruited to the injury site and differentiate into either chondroblasts or osteoblasts precursors, leading to bone repairing and regeneration. Besides these two precursors, the MSCs can also differentiate into adipocyte precursors, skeletal muscle precursors and some other mesodermal cells. With this multilineage potentiality, the MSCs are probably used to cure bone injury and other woundings in the near future. Here we will introduce the recent developments in understanding the mechanism of MSCs action in bone regeneration and repairing.
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Affiliation(s)
- Jin Shao
- Department of Orthopaedics, Shanghai Pudong New Area Gongli Hospital, Second Military Medical University, Shanghai, 200135, China.
| | - Weiwei Zhang
- State Key Laboratory of Oncogenes and Related Genes, Renji-Med X Clinical Stem Cell Research Center, Ren Ji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, 200127, China.
| | - Tieyi Yang
- Department of Orthopaedics, Shanghai Pudong New Area Gongli Hospital, Second Military Medical University, Shanghai, 200135, China.
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22
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Park WS, Sung SI, Ahn SY, Sung DK, Im GH, Yoo HS, Choi SJ, Chang YS. Optimal Timing of Mesenchymal Stem Cell Therapy for Neonatal Intraventricular Hemorrhage. Cell Transplant 2015; 25:1131-44. [PMID: 26440762 DOI: 10.3727/096368915x689640] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
We recently showed that intraventricular transplantation of human umbilical cord blood (UCB)-derived mesenchymal stem cells (MSCs) significantly attenuated posthemorrhagic hydrocephalus (PHH) and brain injury after severe intraventricular hemorrhage (IVH) in newborn rat pups. The purpose of this study was to optimize the timing of MSC transplantation for severe IVH. Severe IVH was induced by injecting 100 µl of blood into each ventricle of Sprague-Dawley rats on postnatal day 4 (P4). Human UCB-derived MSCs (1 × 10(5) cells in 10 µl of normal saline) were transplanted intraventricularly under stereotaxic guidance either early at P6 or late at P11. Serial brain MRIs and behavioral function tests, such as negative geotaxis and rotarod tests, were performed. At P32, brain tissue samples were obtained for histological and biochemical analyses. Intracerebroventricular transplantation of MSCs significantly attenuated the development of PHH, behavioral impairment, increased apoptosis and astrogliosis, reduced corpus callosum thickness and brain myelination, and upregulated inflammatory cytokines including interleukin (IL)-1α, IL-1β, IL-6, and tumor necrosis factor-α (TNF-α) at P6 but not at P11 after induction of severe IVH. Intracerebroventricular transplantation of human UCB-derived MSCs attenuated PHH and brain injury after severe IVH in newborn rats in a time-dependent manner. Significant neuroprotection was only demonstrated when administered early at 2 days after induction but not late at 7 days after induction of severe IVH.
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Affiliation(s)
- Won Soon Park
- Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
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23
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Ahmed M, Cheng M, Cheung IY, Cheung NK. Human derived dimerization tag enhances tumor killing potency of a T-cell engaging bispecific antibody. Oncoimmunology 2015; 4:e989776. [PMID: 26137406 PMCID: PMC4485828 DOI: 10.4161/2162402x.2014.989776] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/14/2014] [Accepted: 11/15/2014] [Indexed: 11/25/2022] Open
Abstract
Bispecific antibodies (BsAbs) have proven highly efficient T cell recruiters for cancer immunotherapy by virtue of one tumor antigen-reactive single chain variable fragment (scFv) and another that binds CD3. In order to enhance the antitumor potency of these tandem scFv BsAbs (tsc-BsAbs), we exploited the dimerization domain of the human transcription factor HNF1α to enhance the avidity of a tsc-BsAb to the tumor antigen disialoganglioside GD2 while maintaining functional monovalency to CD3 to limit potential toxicity. The dimeric tsc-BsAb showed increased avidity to GD2, enhanced T cell mediated killing of neuroblastoma and melanoma cell lines in vitro (32–37 fold), exhibited a near 4-fold improvement in serum half-life, and enhanced tumor ablation in mouse xenograft models. We propose that the use of this HNF1α-derived dimerization tag may be a novel and effective strategy to increase the potency of T-cell engaging antibodies for clinical cancer immunotherapy.
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Affiliation(s)
- Mahiuddin Ahmed
- Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Ming Cheng
- Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - Irene Y Cheung
- Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA
| | - N K Cheung
- Department of Pediatrics; Memorial Sloan Kettering Cancer Center ; New York, NY USA
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24
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Suzuki M, Cheung NKV. Disialoganglioside GD2 as a therapeutic target for human diseases. Expert Opin Ther Targets 2015; 19:349-62. [PMID: 25604432 DOI: 10.1517/14728222.2014.986459] [Citation(s) in RCA: 118] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
INTRODUCTION Ganglioside GD2 is found in vertebrates and invertebrates, overexpressed among pediatric and adult solid tumors, including neuroblastoma, glioma, retinoblastoma, Ewing's family of tumors, rhabdomyosarcoma, osteosarcoma, leiomyosarcoma, liposarcoma, fibrosarcoma, small cell lung cancer and melanoma. It is also found on stem cells, neurons, some nerve fibers and basal layer of the skin. AREAS COVERED GD2 provides a promising clinical target for radiolabeled antibodies, bispecific antibodies, chimeric antigen receptor (CAR)-modified T cells, drug conjugates, nanoparticles and vaccines. Here, we review its biochemistry, normal physiology, role in tumorigenesis, important characteristics as a target, as well as anti-GD2-targeted strategies. EXPERT OPINION Bridging the knowledge gaps in understanding the interactions of GD2 with signaling molecules within the glycosynapses, and the regulation of its cellular expression should improve therapeutic strategies targeting this ganglioside. In addition to anti-GD2 IgG mAbs, their drug conjugates, radiolabeled forms especially when genetically engineered to improve therapeutic index and novel bispecific forms or CARs to retarget T-cells are promising candidates for treating metastatic cancers.
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Affiliation(s)
- Maya Suzuki
- Memorial Sloan Kettering Cancer Center, Department of Pediatrics , 1275 York Avenue, New York, NY 10065 , USA +1 646 888 2313 ; +1 631 422 0452 ;
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25
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Jeoung JY, Nam HY, Kwak J, Jin HJ, Lee HJ, Lee BW, Baek JH, Eom JS, Chang EJ, Shin DM, Choi SJ, Kim SW. A decline in Wnt3a signaling is necessary for mesenchymal stem cells to proceed to replicative senescence. Stem Cells Dev 2015; 24:973-82. [PMID: 25437011 DOI: 10.1089/scd.2014.0273] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Umbilical cord blood-derived mesenchymal stem cells are a promising source of cells for regeneration therapy due to their multipotency, high proliferative capacity, relatively noninvasive collection, and ready availability. However, extended cell culture inevitably triggers cellular senescence-the irreversible arrest of cell division-thereby limiting the proliferative lifespan of adult stem cells. Wnt/β-catenin signaling plays a functional role as a key regulator of self-renewal and differentiation in mesenchymal stem cells (MSCs), and thus Wnt/β-catenin signaling and cellular senescence might be closely connected. Here, we show that the expression levels of canonical Wnt families decrease as MSCs age during subculture. Activation of the Wnt pathway by treatment with Wnt3a-conditioned medium or glycogen synthase kinase 3β inhibitors, such as SB-216763 and 6-bromoindirubin-3'-oxime, delays the progression of cellular senescence as shown by the decrease in the senescence effectors p53 and pRb, lowered senescence-associated β-galactosidase activity, and increased telomerase activity. In contrast, suppression of the Wnt pathway by treatment with dickkopf-1 (an antagonist of the Wnt coreceptor) and β-catenin siRNA transfection promotes senescence in MSCs. Interestingly, the magnitude of the response to enhanced Wnt3a/β-catenin signaling appears to depend on the senescent state during extended culture, particularly after multiple passages. These results suggest that Wnt3a signaling might be a predominant factor that could be used to overcome senescence in long-term cultured MSCs by directly intervening in the proliferative capacity and MSC senescence. The functional role of Wnt3a/β-catenin signaling in hedging cellular senescence may allow the development of new approaches for stem cell-based therapies.
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Affiliation(s)
- Ji Yung Jeoung
- 1 Department of Biochemistry and Molecular Biology, Asan Medical Center, University of Ulsan College of Medicine , Seoul, Korea
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Van Pham P, Phan NK. Production of good manufacturing practice-grade human umbilical cord blood-derived mesenchymal stem cells for therapeutic use. Methods Mol Biol 2015; 1283:73-85. [PMID: 25239529 DOI: 10.1007/7651_2014_125] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/03/2023]
Abstract
Human umbilical cord blood-derived mesenchymal stem cells (UCB-MSCs) are multipotent stem cells that can be differentiated into several specific cell types such as adipocytes, osteoblasts, and chondroblasts. They also were demonstrated to trans-differentiate into other cell lineages such as muscle cells and neurons. Thus, they are considered a promising stem cell source for therapeutic use. Here, we describe a method for production of good manufacturing practice-grade human UCB-MSCs for therapeutic use. The obtained UCB-MSCs are free of allogenous or xenogenous proteins. In addition, these MSCs could maintain the MSC phenotype in long-term culture.
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Affiliation(s)
- Phuc Van Pham
- Laboratory of Stem Cell Research and Application, University of Science, Vietnam National University, Ho Chi Minh City, Vietnam,
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27
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Kucerova L, Zmajkovic J, Toro L, Skolekova S, Demkova L, Matuskova M. Tumor-driven Molecular Changes in Human Mesenchymal Stromal Cells. CANCER MICROENVIRONMENT 2014; 8:1-14. [PMID: 25169041 DOI: 10.1007/s12307-014-0151-9] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/21/2014] [Accepted: 08/07/2014] [Indexed: 12/23/2022]
Abstract
Mesenchymal stromal cells (MSC) exert either tumor-stimulatory or tumor-inhibitory effect. The outcome of the tumor-MSC interaction is dictated by the tumor-specific activating signals. We analyzed the alterations in MSC phenotype in response to stimulation by tumor-secreted paracrine factors. Paracrine factors from human melanoma A375 and glioblastoma 8MGBA cells were used for prolonged culture of MSC to produce derived cells designated DIFF(A)-MSC or DIFF(G)-MSC, respectively. Derived cells were analyzed for the specific surface markers, the expression pattern of MSC markers and fibroblast-specific proteins. Changes in the cell phenotype were evaluated using scratch wound assay and tube formation in vitro; and xenotransplant growth in vivo. Our data show induced expression of vascular endothelial growth factor 2, CD146, fibroblast-specific protein, vimentin and endosialin in DIFF(A)-MSC cells. This indicates their differentiation towards the cells with features of tumor-associated fibroblasts upon stimulation with melanoma-secreted cytokines. Paracrine stimulation in DIFF(G)-MSC led to up-regulation of the genes involved in the MSC differentiation. MSC-specific surface marker characteristics were preserved in derived DIFF(A)-MSC and DIFF(G)-MSC cells. However, we observed increased proportion of CD146 and GD2 (neural ganglioside) positive cells and decreased expression of marker NG2 in the MSC exposed to tumor-conditioned medium. Melanoma-CM increased MSC migration, glioblastoma-CM compromised angiogenic capacity of MSC in vitro and the protumorigenic effect in vivo. Our data directly compare the pleiotropic effects mediated by the malignant cells on the MSC. Secreted paracrine factors from melanoma or glioblastoma differently changed molecular traits in MSC, which explains the dual role of MSC in tumor growth.
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Affiliation(s)
- Lucia Kucerova
- Laboratory of Molecular Oncology, Cancer Research Institute, Slovak Academy of Sciences, Vlarska 7, 833 91, Bratislava, Slovakia,
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28
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Jang HR, Park JH, Kwon GY, Lee JE, Huh W, Jin HJ, Choi SJ, Oh W, Oh HY, Kim YG. Effect of preemptive treatment with human umbilical cord blood-derived mesenchymal stem cells on the development of renal ischemia-reperfusion injury in mice. Am J Physiol Renal Physiol 2014; 307:F1149-61. [PMID: 25143451 DOI: 10.1152/ajprenal.00555.2013] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Human umbilical cord blood-derived mesenchymal stem cells (HUCB-MSCs) have been studied in several models of immune-mediated disease because of their unique immunomodulatory properties. We hypothesized that HUCB-MSCs could suppress the inflammatory response in postischemic kidneys and attenuate early renal injury. In 8- to 10-wk-old male C57BL/6 mice, bilateral ischemia-reperfusion injury (IRI) surgery was performed, and 1 × 10(6) HUCB-MSCs were injected intraperitoneally 24 h before surgery and during reperfusion. Renal functional and histological changes, HUCB-MSC trafficking, leukocyte infiltration, and cytokine expression were analyzed. Renal functional decline and tubular injury after IRI were attenuated by HUCB-MSC treatment. PKH-26-labeled HUCB-MSCs trafficked into the postischemic kidney. Although numbers of CD45-positive leukocytes in the postischemic kidney were comparable between groups, the expression of interferon-γ in the postischemic kidney was suppressed by HUCB-MSC treatment. The rapid decrease in intrarenal VEGF after IRI was markedly mitigated by HUCB-MSC treatment. In inflammatory conditions simulated in a cell culture experiment, VEGF secretion from HUCB-MSCs was substantially enhanced. VEGF inhibitor abolished the renoprotective effect of HUCB-MSCs after IRI. Flow cytometry analysis revealed the decreased infiltration of natural killer T cells and increased number of regulatory T cells in postischemic kidneys. In addition, these effects of HUCB-MSCs on kidney infiltrating mononuclear cells after IRI were attenuated by VEGF inhibitor. HUCB-MSCs attenuated renal injury in mice in the early injury phase after IRI, mainly by humoral effects and secretion of VEGF. Our results suggest a promising role for HUCB-MSCs in the treatment of renal IRI.
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Affiliation(s)
- Hye Ryoun Jang
- Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ji Hyeon Park
- Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ghee Young Kwon
- Department of Pathology, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea; and
| | - Jung Eun Lee
- Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Wooseong Huh
- Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Company Limited, Seoul, Korea
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Company Limited, Seoul, Korea
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Company Limited, Seoul, Korea
| | - Ha Young Oh
- Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Yoon-Goo Kim
- Nephrology Division, Department of Medicine, Samsung Medical Center, Samsung Biomedical Research Institute, Sungkyunkwan University School of Medicine, Seoul, Korea;
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Ahmed M, Hu J, Cheung NKV. Structure Based Refinement of a Humanized Monoclonal Antibody That Targets Tumor Antigen Disialoganglioside GD2. Front Immunol 2014; 5:372. [PMID: 25177320 PMCID: PMC4132262 DOI: 10.3389/fimmu.2014.00372] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 07/21/2014] [Indexed: 12/13/2022] Open
Abstract
Disialoganglioside GD2 is an important target on several pediatric and adult cancer types including neuroblastoma, retinoblastoma, melanoma, small-cell lung cancer, brain tumors, sarcomas, and cancer stem cells. We have utilized structural and computational methods to refine the framework of humanized monoclonal antibody 3F8, the highest affinity anti-GD2 antibody in clinical development. Two constructs (V3 and V5) were designed to enhance stability and minimize potential immunogenicity. Construct V3 contained 12 point mutations and had higher thermal stability and comparable affinity and in vitro tumor cells killing as the parental hu3F8. Construct V5 had nine point mutations to minimize potential immunogenicity, but resulted in weaker thermal stability, weaker antigen binding, and reduced tumor killing potency. When construct V3 was combined with the single point mutation HC:G54I, the resulting V3-Ile construct had enhanced stability, antigen binding, and a nearly sixfold increase in tumor cell killing. The resulting product is a lead candidate for clinical development for the treatment of GD2-positive tumors.
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Affiliation(s)
- Mahiuddin Ahmed
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Jian Hu
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Nai-Kong V. Cheung
- Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA
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30
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Harichandan A, Sivasubramaniyan K, Bühring HJ. Prospective isolation and characterization of human bone marrow-derived MSCs. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2014; 129:1-17. [PMID: 22825720 DOI: 10.1007/10_2012_147] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
Abstract
There is an increasing interest in adult stem cells, especially mesenchymal stem/stromal cells (MSCs), in hematology and regenerative medicine because of the simplicity of isolation and ex vivo expansion of these cells. Conventionally, MSCs are functionally isolated from tissue based on their capacity to adhere to the surface of culture flasks. This isolation procedure is hampered by the unpredictable influence of secreted molecules and interactions with co-cultured hematopoietic and other unrelated cells, as well as by the arbitrarily selected removal time of non-adherent cells prior to the expansion of MSCs. Finally, functionally isolated cells do not provide biological information about the starting population. To circumvent these limitations, several strategies have been developed to facilitate the prospective isolation of MSCs based on the selective expression or absence of surface markers. The isolation and ex vivo expansion of these cells require an adequate quality control of the source and product. Here we summarize the most frequently used markers and introduce new targets for antibody-based isolation and characterization of bone marrow-derived MSCs.
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Affiliation(s)
- A Harichandan
- Division of Haematology, Immunology, Oncology, Rheumatology, and Pulmonology, Department of Internal Medicine II, University Clinic of Tübingen, Tübingen, Germany
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31
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Yuan Y, Pan S, Sun Z, Dan Q, Liu J. Brain-derived neurotrophic factor-modified umbilical cord mesenchymal stem cell transplantation improves neurological deficits in rats with traumatic brain injury. Int J Neurosci 2013; 124:524-31. [DOI: 10.3109/00207454.2013.859144] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
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Ahmed M, Cheung NKV. Engineering anti-GD2 monoclonal antibodies for cancer immunotherapy. FEBS Lett 2013; 588:288-97. [PMID: 24295643 DOI: 10.1016/j.febslet.2013.11.030] [Citation(s) in RCA: 99] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2013] [Revised: 11/25/2013] [Accepted: 11/25/2013] [Indexed: 01/28/2023]
Abstract
Ganglioside GD2 is highly expressed on neuroectoderm-derived tumors and sarcomas, including neuroblastoma, retinoblastoma, melanoma, small cell lung cancer, brain tumors, osteosarcoma, rhabdomyosarcoma, Ewing's sarcoma in children and adolescents, as well as liposarcoma, fibrosarcoma, leiomyosarcoma and other soft tissue sarcomas in adults. Since GD2 expression in normal tissues is restricted to the brain, which is inaccessible to circulating antibodies, and in selected peripheral nerves and melanocytes, it was deemed a suitable target for systemic tumor immunotherapy. Anti-GD2 antibodies have been actively tested in clinical trials for neuroblastoma for over the past two decades, with proven safety and efficacy. The main limitations have been acute pain toxicity associated with GD2 expression on peripheral nerve fibers and the inability of antibodies to treat bulky tumor. Several strategies have been developed to reduce pain toxicity, including bypassing complement activation, using blocking antibodies, or targeting of O-acetyl-GD2 derivative that is not expressed on peripheral nerves. To enhance anti-tumor efficacy, anti-GD2 monoclonal antibodies and fragments have been engineered into immunocytokines, immunotoxins, antibody drug conjugates, radiolabeled antibodies, targeted nanoparticles, T-cell engaging bispecific antibodies, and chimeric antigen receptors. The challenges of these approaches will be reviewed to build a perspective for next generation anti-GD2 therapeutics in cancer therapy.
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Affiliation(s)
- Mahiuddin Ahmed
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA
| | - Nai-Kong V Cheung
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, 1275 York Avenue, New York, NY 10065, USA.
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Engraftment of mouse embryonic stem cells differentiated by default leads to neuroprotection, behaviour revival and astrogliosis in parkinsonian rats. PLoS One 2013; 8:e72501. [PMID: 24069147 PMCID: PMC3772067 DOI: 10.1371/journal.pone.0072501] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2013] [Accepted: 07/10/2013] [Indexed: 12/21/2022] Open
Abstract
We report here protection against rotenone-induced behavioural dysfunction, striatal dopamine depletion and nigral neuronal loss, following intra-striatal transplantation of neurons differentiated from murine embryonic stem cells (mES). mES maintained in serum free medium exhibited increase in neuronal, and decrease in stem cell markers by 7th and 10th days as revealed by RT-PCR and immunoblot analyses. Tyrosine hydroxylase, NURR1, PITX3, LMX1b and c-RET mRNA showed a significant higher expression in differentiated cells than in mES. Dopamine level was increased by 3-fold on 10th day as compared to 7 days differentiated cells. Severity of rotenone-induced striatal dopamine loss was attenuated, and amphetamine-induced unilateral rotations were significantly reduced in animals transplanted with 7 days differentiated cells, but not in animals that received undifferentiated ES transplant. However, the ratio of contralateral to ipsilateral swings in elevated body swing test was significantly reduced in both the transplanted groups, as compared to control. Striatal grafts exhibited the presence of tyrosine hydroxylase positive cells, and the percentage of dopaminergic neurons in the substantia nigra was also found to be higher in the ipsilateral side of 7 days and mES grafted animals. Increased expression of CD11b and IBA-1, suggested a significant contribution of these microglia-derived factors in controlling the limited survival of the grafted cells. Astrocytosis in the grafted striatum, and significant increase in the levels of glial cell line derived neurotrophic factor may have contributed to the recovery observed in the hemiparkinsonian rats following transplantation.
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34
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Jin HJ, Bae YK, Kim M, Kwon SJ, Jeon HB, Choi SJ, Kim SW, Yang YS, Oh W, Chang JW. Comparative analysis of human mesenchymal stem cells from bone marrow, adipose tissue, and umbilical cord blood as sources of cell therapy. Int J Mol Sci 2013; 14:17986-8001. [PMID: 24005862 PMCID: PMC3794764 DOI: 10.3390/ijms140917986] [Citation(s) in RCA: 445] [Impact Index Per Article: 37.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2013] [Revised: 07/18/2013] [Accepted: 08/22/2013] [Indexed: 02/07/2023] Open
Abstract
Various source-derived mesenchymal stem cells (MSCs) have been considered for cell therapeutics in incurable diseases. To characterize MSCs from different sources, we compared human bone marrow (BM), adipose tissue (AT), and umbilical cord blood-derived MSCs (UCB-MSCs) for surface antigen expression, differentiation ability, proliferation capacity, clonality, tolerance for aging, and paracrine activity. Although MSCs from different tissues have similar levels of surface antigen expression, immunosuppressive activity, and differentiation ability, UCB-MSCs had the highest rate of cell proliferation and clonality, and significantly lower expression of p53, p21, and p16, well known markers of senescence. Since paracrine action is the main action of MSCs, we examined the anti-inflammatory activity of each MSC under lipopolysaccharide (LPS)-induced inflammation. Co-culture of UCB-MSCs with LPS-treated rat alveolar macrophage, reduced expression of inflammatory cytokines including interleukin-1α (IL-1α), IL-6, and IL-8 via angiopoietin-1 (Ang-1). Using recombinant Ang-1 as potential soluble paracrine factor or its small interference RNA (siRNA), we found that Ang-1 secretion was responsible for this beneficial effect in part by preventing inflammation. Our results demonstrate that primitive UCB-MSCs have biological advantages in comparison to adult sources, making UCB-MSCs a useful model for clinical applications of cell therapy.
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Affiliation(s)
- Hye Jin Jin
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
- Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea; E-Mail:
| | - Yun Kyung Bae
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Miyeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Soon-Jae Kwon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Hong Bae Jeon
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Soo Jin Choi
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Seong Who Kim
- Molecular Biology, University of Ulsan College of Medicine, Seoul 138-736, Korea; E-Mail:
| | - Yoon Sun Yang
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Wonil Oh
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
| | - Jong Wook Chang
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Korea; E-Mails: (H.J.J.); (Y.K.B.); (M.K.); (S.-J.K.); (H.B.J.); (S.J.C.); (Y.S.Y.); (W.O.)
- Author to whom correspondence should be addressed; E-Mail: ; Tel.: +82-2-3465-6771; Fax: +82-2-475-1991
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Calloni R, Cordero EAA, Henriques JAP, Bonatto D. Reviewing and updating the major molecular markers for stem cells. Stem Cells Dev 2013; 22:1455-76. [PMID: 23336433 PMCID: PMC3629778 DOI: 10.1089/scd.2012.0637] [Citation(s) in RCA: 129] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022] Open
Abstract
Stem cells (SC) are able to self-renew and to differentiate into many types of committed cells, making SCs interesting for cellular therapy. However, the pool of SCs in vivo and in vitro consists of a mix of cells at several stages of differentiation, making it difficult to obtain a homogeneous population of SCs for research. Therefore, it is important to isolate and characterize unambiguous molecular markers that can be applied to SCs. Here, we review classical and new candidate molecular markers that have been established to show a molecular profile for human embryonic stem cells (hESCs), mesenchymal stem cells (MSCs), and hematopoietic stem cells (HSCs). The commonly cited markers for embryonic ESCs are Nanog, Oct-4, Sox-2, Rex-1, Dnmt3b, Lin-28, Tdgf1, FoxD3, Tert, Utf-1, Gal, Cx43, Gdf3, Gtcm1, Terf1, Terf2, Lefty A, and Lefty B. MSCs are primarily identified by the expression of CD13, CD29, CD44, CD49e, CD54, CD71, CD73, CD90, CD105, CD106, CD166, and HLA-ABC and lack CD14, CD31, CD34, CD45, CD62E, CD62L, CD62P, and HLA-DR expression. HSCs are mainly isolated based on the expression of CD34, but the combination of this marker with CD133 and CD90, together with a lack of CD38 and other lineage markers, provides the most homogeneous pool of SCs. Here, we present new and alternative markers for SCs, along with microRNA profiles, for these cells.
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Affiliation(s)
- Raquel Calloni
- Departamento de Biologia Molecular e Biotecnologia, Centro de Biotecnologia da Universidade Federal do Rio Grande do Sul, Universidade Federal do Rio Grande do Sul (UFRGS), Porto Alegre, Brazil
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Sivasubramaniyan K, Lehnen D, Ghazanfari R, Sobiesiak M, Harichandan A, Mortha E, Petkova N, Grimm S, Cerabona F, de Zwart P, Abele H, Aicher WK, Faul C, Kanz L, Bühring HJ. Phenotypic and functional heterogeneity of human bone marrow- and amnion-derived MSC subsets. Ann N Y Acad Sci 2012; 1266:94-106. [PMID: 22901261 DOI: 10.1111/j.1749-6632.2012.06551.x] [Citation(s) in RCA: 69] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
Bone marrow-derived mesenchymal stromal/stem cells (MSCs) are nonhematopoietic cells that are able to differentiate into osteoblasts, adipocytes, and chondrocytes. In addition, they are known to participate in niche formation for hematopoietic stem cells and to display immunomodulatory properties. Conventionally, these cells are functionally isolated from tissue based on their capacity to adhere to the surface of culture flasks. This isolation procedure is hampered by the unpredictable influence of secreted molecules, the interactions between cocultured hematopoietic and other unrelated cells, and by the arbitrarily selected removal time of nonadherent cells before the expansion of MSCs. Finally, functionally isolated cells do not provide biological information about the starting population. To circumvent these limitations, several strategies have been developed to facilitate the prospective isolation of MSCs based on the selective expression, or absence, of surface markers. In this report, we summarize the most frequently used markers and introduce new targets for antibody-based isolation procedures of primary bone marrow- and amnion-derived MSCs.
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Affiliation(s)
- Kavitha Sivasubramaniyan
- Department of Internal Medicine II, Division of Hematology, Immunology, Oncology, Rheumatology and Pulmonology, University Clinic of Tübingen, Tübingen, Germany
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Orentas RJ, Lee DW, Mackall C. Immunotherapy targets in pediatric cancer. Front Oncol 2012; 2:3. [PMID: 22645714 PMCID: PMC3355840 DOI: 10.3389/fonc.2012.00003] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2011] [Accepted: 01/04/2012] [Indexed: 01/26/2023] Open
Abstract
Immunotherapy for cancer has shown increasing success and there is ample evidence to expect that progress gleaned in immune targeting of adult cancers can be translated to pediatric oncology. This manuscript reviews principles that guide selection of targets for immunotherapy of cancer, emphasizing the similarities and distinctions between oncogene-inhibition targets and immune targets. It follows with a detailed review of molecules expressed by pediatric tumors that are already under study as immune targets or are good candidates for future studies of immune targeting. Distinctions are made between cell surface antigens that can be targeted in an MHC independent manner using antibodies, antibody derivatives, or chimeric antigen receptors versus intracellular antigens which must be targeted with MHC restricted T cell therapies. Among the most advanced immune targets for childhood cancer are CD19 and CD22 on hematologic malignancies, GD2 on solid tumors, and NY-ESO-1 expressed by a majority of synovial sarcomas, but several other molecules reviewed here also have properties which suggest that they too could serve as effective targets for immunotherapy of childhood cancer.
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Affiliation(s)
- Rimas J Orentas
- Pediatric Oncology Branch, National Cancer Institute, National Institutes of Health Bethesda, MD, USA
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Abstract
NSCs (neural stem cells) are undifferentiated neural cells endowed with a high potential for proliferation and a capacity for self-renewal with retention of multipotency to differentiate into neurons and glial cells. It has been recently reported that GD3, a b-series ganglioside, is a marker molecule for identifying and isolating mouse NSCs. However, the expression of gangliosides in human NSCs is largely unknown. In the present study, we analysed the expression of gangliosides, GD2 and GD3, in human NSCs that were isolated from human brains at gestational week 17 in the form of neurospheres, which are floating clonal aggregates formed by NSCs in vitro. Employing immunocytochemistry, we found that human NSCs were strongly reactive to anti-GD2 antibody and relatively weakly reactive to anti-GD3 antibody. Treatment of these cells with an organic solvent such as 100% methanol, which selectively removes glycolipids from plasma membrane, abolished the immunoreactivity with those antibodies, indicating that the reactivity was due to GD2 and GD3, but not to GD2-/GD3-like glycoproteins or proteoglycans. The immunoreactivity of human NSCs to antibody against SSEA-1 (stage-specific embryonic antigen-1), a well-known carbohydrate antigen of NSCs, was not decreased by the treatment with 100% methanol, indicating that SSEA-1 is mainly carried by glycoproteins and/or proteoglycans in human NSCs. Our study suggests that GD2 and GD3 can be marker gangliosides for identifying human NSCs.
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Kim JY, Kim DH, Kim DS, Kim JH, Jeong SY, Jeon HB, Lee EH, Yang YS, Oh W, Chang JW. Galectin-3 secreted by human umbilical cord blood-derived mesenchymal stem cells reduces amyloid-beta42 neurotoxicity in vitro. FEBS Lett 2010; 584:3601-8. [PMID: 20655311 DOI: 10.1016/j.febslet.2010.07.028] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2010] [Revised: 07/13/2010] [Accepted: 07/16/2010] [Indexed: 01/07/2023]
Abstract
In this study, we found that expression and secretion of galectin-3 (GAL-3) were upregulated by amyloid-beta42 (Abeta42) exposure in human umbilical cord blood-derived mesenchymal stem cell (hUCB-MSC) without cell death. Abeta42-exposed rat primary cortical neuronal cells co-treated with recombinant GAL-3 were protected from neuronal death in a dose-dependent manner. hUCB-MSCs were cocultured with Abeta42-exposed rat primary neuronal cells or the neuroblastoma cell line, SH-SY5Y in a Transwell chamber. Coculture of hUCB-MSCs reduced cell death of Abeta42-exposed neurons and SH-SY5Y cells. This neuroprotective effect of hUCB-MSCs was reduced significantly by GAL-3 siRNA. These data suggested that hUCB-MSC-derived GAL-3 is a survival factor against Abeta42 neurotoxicity.
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Affiliation(s)
- Ju-Yeon Kim
- Biomedical Research Institute, MEDIPOST Co., Ltd., Seoul 137-874, Republic of Korea
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