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Chen S, Wu P, Zhang T, Zhang J, Gao H. Global scientific trends on the islet transplantation in the 21st century: A bibliometric and visualized analysis. Medicine (Baltimore) 2024; 103:e37945. [PMID: 38669398 PMCID: PMC11049693 DOI: 10.1097/md.0000000000037945] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2023] [Accepted: 03/29/2024] [Indexed: 04/28/2024] Open
Abstract
BACKGROUND Islet transplantation (IT) has emerged as a significant research area for the treatment of diabetes mellitus and has witnessed a surge in scholarly attention. Despite its growing importance, there is a lack of bibliometric analyses that encapsulate the evolution and scientific underpinnings of this field. This study aims to fill this gap by conducting a comprehensive bibliometric analysis to delineate current research hotspots and forecast future trajectories within the IT domain with a particular focus on evidence-based medicine practices. METHODS This analysis scrutinized literature from January 1, 2000, to October 1, 2023, using the Web of Science Core Collection (WoSCC). Employing bibliometric tools such as VOSviewer, CiteSpace, and the R package "bibliometrix," we systematically evaluated the literature to uncover scientific trends and collaboration networks in IT research. RESULTS The analysis revealed 8388 publications from 82 countries, predominantly the United States and China. However, global cross-institutional collaboration in IT research requires further strengthening. The number of IT-related publications has increased annually. Leading research institutions in this field include Harvard University, the University of Alberta, the University of Miami, and the University of Minnesota. "Transplantation" emerges as the most frequently cited journal in this area. Shapiro and Ricordi were the most prolific authors, with 126 and 121 publications, respectively. Shapiro also led to co-citations, totaling 4808. Key research focuses on IT sites and procedures as well as novel therapies in IT. Emerging research hotspots are identified by terms like "xenotransplantation," "apoptosis," "stem cells," "immunosuppression," and "microencapsulation." CONCLUSIONS The findings underscore a mounting anticipation for future IT research, which is expected to delve deeper into evidence-based methodologies for IT sites, procedures, and novel therapeutic interventions. This shift toward evidence-based medicine underscores the field's commitment to enhancing the efficacy and safety of IT for diabetes treatment, signaling a promising direction for future investigations aimed at optimizing patient outcomes.
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Affiliation(s)
- Sheng Chen
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - PeiZhong Wu
- Graduate School, Guangxi University of Chinese Medicine, Nanning, China
| | - Ting Zhang
- Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning, China
| | - Jianqiang Zhang
- Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning, China
| | - Hongjun Gao
- Ruikang Hospital, Guangxi University of Chinese Medicine, Nanning, China
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Jiang Z, Xu Y, Fu M, Zhu D, Li N, Yang G. Genetically modified cell spheroids for tissue engineering and regenerative medicine. J Control Release 2023; 354:588-605. [PMID: 36657601 DOI: 10.1016/j.jconrel.2023.01.033] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2022] [Revised: 01/11/2023] [Accepted: 01/12/2023] [Indexed: 01/21/2023]
Abstract
Cell spheroids offer cell-to-cell interactions and show advantages in survival rate and paracrine effect to solve clinical and biomedical inquiries ranging from tissue engineering and regenerative medicine to disease pathophysiology. Therefore, cell spheroids are ideal vehicles for gene delivery. Genetically modified spheroids can enhance specific gene expression to promote tissue regeneration. Gene deliveries to cell spheroids are via viral vectors or non-viral vectors. Some new technologies like CRISPR/Cas9 also have been used in genetically modified methods to deliver exogenous gene to the host chromosome. It has been shown that genetically modified cell spheroids had the potential to differentiate into bone, cartilage, vascular, nerve, cardiomyocytes, skin, and skeletal muscle as well as organs like the liver to replace the diseased organ in the animal and pre-clinical trials. This article reviews the recent articles about genetically modified spheroid cells and explains the fabrication, applications, development timeline, limitations, and future directions of genetically modified cell spheroid.
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Affiliation(s)
- Zhiwei Jiang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Yi Xu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Mengdie Fu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Danji Zhu
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Na Li
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China
| | - Guoli Yang
- Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Hangzhou 310000, China.
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Sadeghi B, Witkamp M, Schefberger D, Arbman A, Ringdén O. Immunomodulation by placenta-derived decidua stromal cells. Role of histocompatibility, accessory cells and freeze-thawing. Cytotherapy 2023; 25:68-75. [PMID: 36333233 DOI: 10.1016/j.jcyt.2022.10.004] [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: 03/27/2022] [Revised: 09/15/2022] [Accepted: 10/07/2022] [Indexed: 11/13/2022]
Abstract
BACKGROUND AIMS Human placenta-derived decidua stromal cells (DSCs) are newly introduced stromal cells that have successfully been used in several clinical trials for the treatment of acute inflammatory diseases. Despite published data about DSCs, deeper exploration of mechanisms of action and crosstalk with other immune cells need to be explored. METHODS In mixed lymphocyte culture (MLC), the splenocytes from Balb/c or B6 mice were stimulated using mitogen (concanavalin A), allogeneic (B6 or Balb/c splenocytes) or xenogeneic activation with human peripheral blood mononuclear cells. RESULTS When 10% of the mouse bone marrow-derived-MSC, being autologous, allogeneic or haploidentical (from F1), was added, >95% inhibition was seen. Using human (h)-DSCs, the inhibitory capacity was a median 68% as a xenogeneic immunomodulatory cell when used in mitogen and allogeneic setting in mice MLC. However, when human peripheral blood mononuclear cells were used as stimulator for mouse splenocyte (xenogeneic MLC), hDSC showed a median inhibition of 88%. We explored the presence and function of monocytes in the immunomodulatory function of stromal cells. CD14+ monocyte cells reduced the immunosuppressive effect by hDSC. hDSCs did not show any inhibitory effect on natural killer cell activation and proliferation by interleukin-2. In contrast DSCs increased natural killer proliferation by a median of 58%. Fresh or frozen-thawed hDSCs had similar inhibitory effects on human T-cell proliferation (both allo-stimulation and mitogen stimulation) in vitro. Cell viability at room temperature during 24 h was similar using fresh or freeze-thawed DSCs. CONCLUSIONS To conclude, histocompatibility and CD14+ monocyte cells had an impact on hDSC immunomodulation but frozen-thawed or freshly prepared cells did not.
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Affiliation(s)
- Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Huddinge, Sweden.
| | - Myrèse Witkamp
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Huddinge, Sweden
| | - Dominik Schefberger
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Huddinge, Sweden
| | - Anna Arbman
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Huddinge, Sweden
| | - Olle Ringdén
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Huddinge, Sweden
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4
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Thamm K, Möbus K, Towers R, Baertschi S, Wetzel R, Wobus M, Segeletz S. A chemically defined biomimetic surface for enhanced isolation efficiency of high-quality human mesenchymal stromal cells under xenogeneic/serum-free conditions. Cytotherapy 2022; 24:1049-1059. [PMID: 35931601 DOI: 10.1016/j.jcyt.2022.06.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 05/23/2022] [Accepted: 06/10/2022] [Indexed: 11/15/2022]
Abstract
BACKGROUND AIMS Mesenchymal stromal cells (MSCs) are one of the most frequently used cell types in regenerative medicine and cell therapy. Generating sufficient cell numbers for MSC-based therapies is constrained by (i) their low abundance in tissues of origin, which imposes the need for significant ex vivo cell expansion; (ii) donor-specific characteristics, including MSC frequency/quality, that decline with disease state and increasing age; and (iii) cellular senescence, which is promoted by extensive cell expansion and results in decreased therapeutic functionality. The final yield of a manufacturing process is therefore primarily determined by the applied isolation procedure and its efficiency in isolating therapeutically active cells from donor tissue. To date, MSCs are predominantly isolated using media supplemented with either serum or its derivatives, which poses safety and consistency issues. METHODS To overcome these limitations while enabling robust MSC production with constant high yield and quality, the authors developed a chemically defined biomimetic surface coating called isoMATRIX (denovoMATRIX GmbH, Dresden, Germany) and tested its performance during isolation of MSCs. RESULTS The isoMATRIX facilitates the isolation of significantly higher numbers of MSCs in xenogeneic (xeno)/serum-free and chemically defined conditions. The isolated cells display a smaller cell size and higher proliferation rate than those derived from a serum-containing isolation procedure and a strong immunomodulatory capacity. The high proliferation rates can be maintained up to 5 passages after isolation and cells even benefit from a switch towards a proliferation-specific MSC matrix (myMATRIX MSC) (denovoMATRIX GmbH, Dresden, Germany). CONCLUSION In sum, isoMATRIX promotes enhanced xeno/serum-free and chemically defined isolation of human MSCs and supports consistent and reliable cell performance for improved stem cell-based therapies.
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Affiliation(s)
| | - Kristin Möbus
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
| | - Russell Towers
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
| | | | | | - Manja Wobus
- Universitätskrankenhaus Carl Gustav Carus der Technischen Universität Dresden, Dresden, Germany
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Ringdén O, Moll G, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells for Enhancing Hematopoietic Engraftment and Treatment of Graft-Versus-Host Disease, Hemorrhages and Acute Respiratory Distress Syndrome. Front Immunol 2022; 13:839844. [PMID: 35371003 PMCID: PMC8973075 DOI: 10.3389/fimmu.2022.839844] [Citation(s) in RCA: 43] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/17/2022] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) possess profound immunomodulatory and regenerative properties that are of clinical use in numerous clinical indications with unmet medical need. Common sources of MSCs include among others, bone marrow (BM), fat, umbilical cord, and placenta-derived decidua stromal cells (DSCs). We here summarize our more than 20-years of scientific experience in the clinical use of MSCs and DSCs in different clinical settings. BM-MSCs were first explored to enhance the engraftment of autografts in hematopoietic cell transplantation (HCT) and osteogenesis imperfecta around 30 years ago. In 2004, our group reported the first anti-inflammatory use of BM-MSCs in a child with grade IV acute graft-versus-host disease (GvHD). Subsequent studies have shown that MSCs appear to be more effective in acute than chronic GvHD. Today BM-MSC-therapy is registered for acute GvHD in Japan and for GvHD in children in Canada and New Zeeland. MSCs first home to the lung following intravenous injection and exert strong local and systemic immunomodulatory effects on the host immune system. Thus, they were studied for ameliorating the cytokine storm in acute respiratory distress syndrome (ARDS). Both, MSCs and DSCs were used to treat SARS-CoV-2 coronavirus-induced disease 2019 (COVID-19)-induced ARDS. In addition, they were also used for other novel indications, such as pneumomediastinum, colon perforation, and radiculomyelopathy. MSC and DSCs trigger coagulation and were thus explored to stop hemorrhages. DSCs appear to be more effective for acute GvHD, ARDS, and hemorrhages, but randomized studies are needed to prove superiority. Stromal cell infusion is safe, well tolerated, and only gives rise to a slight fever in a limited number of patients, but no major side effects have been reported in multiple safety studies and metaanalysis. In this review we summarize current evidence from in vitro studies, animal models, and importantly our clinical experience, to support stromal cell therapy in multiple clinical indications. This encloses MSC's effects on the immune system, coagulation, and their safety and efficacy, which are discussed in relation to prominent clinical trials within the field.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
| | - Guido Moll
- Berlin Institute of Health (BIH) Center for Regenerative Therapies (BCRT) and Berlin-Brandenburg School for Regenerative Therapies (BSRT), Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, All Charité Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
| | - Britt Gustafsson
- Department of Women’s and Children’s Health, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research Group, Department of Clinical Sciences, Intervention and Technology (CLNTEC), Division of Pediatrics, Karolinska Institutet, Stockholm, Sweden
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Mezey É. Human Mesenchymal Stem/Stromal Cells in Immune Regulation and Therapy. Stem Cells Transl Med 2022; 11:114-134. [PMID: 35298659 PMCID: PMC8929448 DOI: 10.1093/stcltm/szab020] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2021] [Accepted: 11/07/2021] [Indexed: 07/29/2023] Open
Abstract
Studies of mesenchymal stem (or stromal) cells (MSCs) have moved from bedside to bench and back again. The stromal cells or fibroblasts are found in all tissues and participate in building the extracellular matrix (ECM). Bone marrow (BM)-derived MSCs have been studied for more than 50 years and have multiple roles. They function as stem cells and give rise to bone, cartilage, and fat in the BM (these are stem cells); support hematopoiesis (pericytes); and participate in sensing environmental changes and balancing pro- and anti-inflammatory conditions. In disease states, they migrate to sites of injury and release cytokines, hormones, nucleic acids depending on the microenvironment they find. Clinicians have begun to exploit these properties of BM, adipose tissue, and umbilical cord MSCs because they are easy to harvest and expand in culture. In this review, I describe the uses to which MSCs have been put, list ongoing clinical trials by organ system, and outline how MSCs are thought to regulate the innate and adaptive immune systems. I will discuss some of the reasons why clinical applications are still lacking. Much more work will have to be done to find the sources, doses, and culture conditions needed to exploit MSCs optimally and learn their healing potential. They are worth the effort.
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Affiliation(s)
- Éva Mezey
- Corresponding author: Éva Mezey, MD, PhD, Head, Adult Stem Cell Section, NIH, NIDCR, Bldg 30, Rm 523, Bethesda, MD 20892, USA . Tel: 1 301 435 5635;
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Beksaç B, Gleason L, Baik S, Ringe JM, Porcu P, Nikbakht N. Dermal fibroblasts promote cancer cell proliferation and exhibit fibronectin overexpression in early mycosis fungoides. J Dermatol Sci 2022; 106:53-60. [PMID: 35331619 PMCID: PMC9133159 DOI: 10.1016/j.jdermsci.2022.03.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 02/07/2022] [Accepted: 03/13/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Mycosis fungoides (MF) is caused by proliferation of malignant T-cells in the skin and may progress to involve blood, lymph nodes, and viscera. While the skin microenvironment is essential for the initiation and progression of MF in early stages, little is known about the impact of skin stroma on the growth and survival of malignant lymphocytes. OBJECTIVE We investigated the effect of dermal fibroblasts and their product, fibronectin, on the survival and proliferation of malignant MF cells. METHODS Fibroblasts and malignant MF CD4 T-cells were isolated from skin of patients with early-stage MF. Fibroblast-lymphocyte co-culture experiments and lymphocyte cultures on fibronectin-coated plates were established utilizing the cells derived from lesional skin, blood, and MF cell lines. The survival and proliferation rates of lymphocytes were assessed via Annexin V and carboxyfluorescein succinimidyl ester assays respectively. Additionally, integrin and fibronectin expressions in MF skin were assessed via immunofluorescence. RESULTS We found that dermal fibroblasts increased the proliferation rates of MF cells, but not normal skin or blood CD4 T-cells. However, fibroblasts did not rescue MF cells from apoptosis in co-cultures. In MF skin, we found an overexpression of a fibronectin isoform not normally found in healthy skin. MF cells expressed fibronectin-binding integrins and adhered to fibronectin but did not exhibit adhesion-mediated survival via fibronectin-integrin interactions. CONCLUSION Overall, our results suggest a direct role for fibroblasts, independent of fibronectin-mediated adhesion, in promoting MF cell proliferation. These findings have implications in understanding and targeting the malignant skin stromal microenvironment in cutaneous lymphomas.
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Farrokhi A, Rahavi M, Jo S, Jalili R, Lim CJ, Ghahsary A, Reid GSD. Inflammatory Immune Responses Trigger Rejection of Allogeneic Fibroblasts Transplanted into Mouse Skin. Cell Transplant 2022; 31:9636897221113803. [PMID: 35912954 PMCID: PMC9340901 DOI: 10.1177/09636897221113803] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Fibroblasts, or their homolog stromal cells, are present in most tissues and play an essential role in tissue homeostasis and regeneration. As a result, fibroblast-based strategies have been widely employed in tissue engineering. However, while considered to have immunosuppressive properties, the survival and functionality of allogeneic fibroblasts after transplantation remain controversial. Here, we evaluated innate and adaptive immune responses against allogeneic fibroblasts following intradermal injection into different immune-deficient mouse strains. While allogeneic fibroblasts were rejected 1 week after transplantation in immunocompetent mice, rejection did not occur in immunodeficient γ chain–deficient NOD-SCID (NSG) mice. T-cell- and B-cell-deficient RAG1 knockout mice showed greater loss of fibroblasts by day 5 after transplantation compared with NSG mice (P ≤ 0.05) but prolonged persistence compared with wild-type recipient (P ≤ 0.005). Loss of fibroblasts correlated with the expression of proinflammatory chemokine genes and infiltration of myeloid cells in the transplantation site. Depletion of macrophages and neutrophils delayed rejection, revealing the role of innate immune cells in an early elimination of fibroblasts that is followed by T-cell-mediated rejection in the second week. These findings indicate that the application of allogeneic fibroblasts in tissue engineering products requires further improvements to overcome cell rejection by innate and adaptive immune cells.
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Affiliation(s)
- Ali Farrokhi
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
| | - MohammadReza Rahavi
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Sumin Jo
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
| | - Reza Jalili
- Burn & Wound Healing Research Group, Division of Plastic Surgery, Department of Surgery and International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, BC, Canada
| | - C. James Lim
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
| | - Aziz Ghahsary
- Burn & Wound Healing Research Group, Division of Plastic Surgery, Department of Surgery and International Collaboration on Repair Discoveries, The University of British Columbia, Vancouver, BC, Canada
| | - Gregor S. D. Reid
- Michael Cuccione Childhood Cancer Research Program, BC Children’s Hospital Research Institute, Vancouver, BC, Canada
- Department of Pediatrics, The University of British Columbia, Vancouver, BC, Canada
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Soni N, Gupta S, Rawat S, Krishnakumar V, Mohanty S, Banerjee A. MicroRNA-Enriched Exosomes from Different Sources of Mesenchymal Stem Cells Can Differentially Modulate Functions of Immune Cells and Neurogenesis. Biomedicines 2021; 10:biomedicines10010069. [PMID: 35052749 PMCID: PMC8772751 DOI: 10.3390/biomedicines10010069] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2021] [Revised: 12/02/2021] [Accepted: 12/02/2021] [Indexed: 01/10/2023] Open
Abstract
Adult Mesenchymal stem cells-derived exosomes carry several biologically active molecules that play prominent roles in controlling disease manifestations. The content of these exosomes, their functions, and effect on the immune cells may differ depending on their tissue sources. Therefore, in this study, we purified the exosomes from three different sources and, using the RNA-Seq approach, highly abundant microRNAs were identified and compared between exosomes and parental cells. The effects of exosomes on different immune cells were studied in vitro by incubating exosomes with PBMC and neutrophils and assessing their functions. The expression levels of several miRNAs varied within the different MSCs and exosomes. Additionally, the expression profile of most of the miRNAs was not similar to that of their respective sources. Exosomes isolated from different sources had different abilities to induce the process of neurogenesis and angiogenesis. Moreover, these exosomes demonstrated their varying effect on PBMC proliferation, neutrophil survival, and NET formation, highlighting their versatility and broad interaction with immune cells. The knowledge gained from this study will improve our understanding of the miRNA landscape of exosomes from hMSCs and provide a resource for further improving our understanding of exosome cargo and their interaction with immune cells.
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Affiliation(s)
- Naina Soni
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
| | - Suchi Gupta
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
| | - Surender Rawat
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
| | - Vishnu Krishnakumar
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
| | - Sujata Mohanty
- DBT-Centre of Excellence for Stem Cell Research, Stem Cell Facility, All India Institute of Medical Sciences, New Delhi 110029, India; (S.G.); (V.K.)
- Correspondence: (S.M.); (A.B.)
| | - Arup Banerjee
- Laboratory of Virology, Regional Centre for Biotechnology, Faridabad 121001, India; (N.S.); (S.R.)
- Correspondence: (S.M.); (A.B.)
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10
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Okić-Đorđević I, Obradović H, Kukolj T, Petrović A, Mojsilović S, Bugarski D, Jauković A. Dental mesenchymal stromal/stem cells in different microenvironments— implications in regenerative therapy. World J Stem Cells 2021; 13:1863-1880. [PMID: 35069987 PMCID: PMC8727232 DOI: 10.4252/wjsc.v13.i12.1863] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2021] [Revised: 06/15/2021] [Accepted: 11/25/2021] [Indexed: 02/06/2023] Open
Abstract
Current research data reveal microenvironment as a significant modifier of physical functions, pathologic changes, as well as the therapeutic effects of stem cells. When comparing regeneration potential of various stem cell types used for cytotherapy and tissue engineering, mesenchymal stem cells (MSCs) are currently the most attractive cell source for bone and tooth regeneration due to their differentiation and immunomodulatory potential and lack of ethical issues associated with their use. The microenvironment of donors and recipients selected in cytotherapy plays a crucial role in regenerative potential of transplanted MSCs, indicating interactions of cells with their microenvironment indispensable in MSC-mediated bone and dental regeneration. Since a variety of MSC populations have been procured from different parts of the tooth and tooth-supporting tissues, MSCs of dental origin and their achievements in capacity to reconstitute various dental tissues have gained attention of many research groups over the years. This review discusses recent advances in comparative analyses of dental MSC regeneration potential with regards to their tissue origin and specific microenvironmental conditions, giving additional insight into the current clinical application of these cells.
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Affiliation(s)
- Ivana Okić-Đorđević
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Hristina Obradović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Tamara Kukolj
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Anđelija Petrović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Slavko Mojsilović
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Diana Bugarski
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
| | - Aleksandra Jauković
- Laboratory for Experimental Hematology and Stem Cells, Institute for Medical Research, University of Belgrade, Belgrade 11129, Serbia
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11
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Delinassios JG, Hoffman RM. The cancer-inhibitory effects of proliferating tumor-residing fibroblasts. Biochim Biophys Acta Rev Cancer 2021; 1877:188673. [PMID: 34953931 DOI: 10.1016/j.bbcan.2021.188673] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2021] [Revised: 12/09/2021] [Accepted: 12/17/2021] [Indexed: 11/19/2022]
Abstract
Initiation, local progression, and metastasis of cancer are associated with specific morphological, molecular, and functional changes in the extracellular matrix and the fibroblasts within the tumor microenvironment (TME). In the early stages of tumor development, fibroblasts are an obstacle that cancer cells must surpass or nullify to progress. Thus, in early tumor progression, specific signaling from cancer cells activates bio-pathways, which abolish the innate anticancer properties of fibroblasts and convert a high proportion of them to tumor-promoting cancer-associated fibroblasts (CAFs). Following this initial event, a wide spectrum of gene expression changes gradually leads to the development of a stromal fibroblast population with complex heterogeneity, creating fibroblast subtypes with characteristic profiles, which may alternate between being tumor-promotive and tumor-suppressive, topologically and chronologically in the TME. These fibroblast subtypes form the tumor's histological landscape including areas of cancer growth, inflammation, angiogenesis, invasion fronts, proliferating and non-proliferating fibroblasts, cancer-cell apoptosis, fibroblast apoptosis, and necrosis. These features reflect general deregulation of tissue homeostasis within the TME. This review discusses fundamental and current knowledge that has established the existence of anticancer fibroblasts within the various interacting elements of the TME. It is proposed that the maintenance of fibroblast proliferation is an essential parameter for the activation of their anticancer capacity, similar to that by which normal fibroblasts would be activated in wound repair, thus maintaining tissue homeostasis. Encouragement of research in this direction may render new means of cancer therapy and a greater understanding of tumor progression.
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Affiliation(s)
- John G Delinassios
- International Institute of Anticancer Research, 1(st) km Kapandritiou-Kalamou Rd., Kapandriti, 19014 Attica, Greece.
| | - Robert M Hoffman
- Department of Surgery, University of California, 9300 Campus Point Drive, La Jolla, CA 92037, USA; AntiCancer Inc., 7917 Ostrow St, San Diego, CA 92111, USA.
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12
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Targeting of Janus Kinases Limits Pro-Inflammatory but Also Immunosuppressive Circuits in the Crosstalk between Synovial Fibroblasts and Lymphocytes. Biomedicines 2021; 9:biomedicines9101413. [PMID: 34680530 PMCID: PMC8533088 DOI: 10.3390/biomedicines9101413] [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: 08/30/2021] [Revised: 10/01/2021] [Accepted: 10/04/2021] [Indexed: 12/29/2022] Open
Abstract
Crosstalk between synovial fibroblasts (SF) and immune cells plays a central role in the development of rheumatoid arthritis (RA). Janus kinase inhibitors (JAKi) have proven efficacy in the treatment of RA, although clinical responses are heterogeneous. Currently, little is known regarding how JAKi affect pro- and anti-inflammatory circuits in the bidirectional interplay between SF and immune cells. Here, we examined the effects of tofacitinib, baricitinib and upadacitinib on crosstalk between SF and T or B lymphocytes in vitro and compared them with those of biologic disease modifying anti-rheumatic drugs (bDMARDs). JAKi dose-dependently suppressed cytokine secretion of T helper (Th) cells and decreased interleukin (IL)-6 and matrix metalloproteinase (MMP)3 secretion of SF stimulated by Th cells. Importantly, JAK inhibition attenuated the enhanced memory response of chronically stimulated SF. Vice versa, JAKi reduced the indoleamine-2,3-dioxygenase (IDO)1-mediated suppression of T cell-proliferation by SF. Remarkably, certain bDMARDs were as efficient as JAKi in suppressing the IL-6 and MMP3 secretion of SF stimulated by Th (adalimumab, secukinumab) or B cells (canakinumab) and combining bDMARDs with JAKi had synergistic effects. In conclusion, JAKi limit pro-inflammatory circuits in the crosstalk between SF and lymphocytes; however, they also weaken the immunosuppressive functions of SF. Both effects were dose-dependent and may contribute to heterogeneity in clinical response to treatment.
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Shrestha M, Nguyen TT, Park J, Choi JU, Yook S, Jeong JH. Immunomodulation effect of mesenchymal stem cells in islet transplantation. Biomed Pharmacother 2021; 142:112042. [PMID: 34403963 DOI: 10.1016/j.biopha.2021.112042] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 08/06/2021] [Accepted: 08/09/2021] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells (MSCs) therapy has brought a great enthusiasm to the treatment of various immune disorders, tissue regeneration and transplantation therapy. MSCs are being extensively investigated for their immunomodulatory actions. MSCs can deliver immunomodulatory signals to inhibit allogeneic T cell immune responses by downregulating pro-inflammatory cytokines and increasing regulatory cytokines and growth factors. Islet transplantation is a therapeutic alternative to the insulin therapy for the treatment of type 1 diabetes mellitus (T1DM). However, the acute loss of islets due to the lack of vasculature and hypoxic milieu in the immediate post-transplantation period may lead to treatment failure. Moreover, despite the use of potent immunosuppressive drugs, graft failure persists because of immunological rejection. Many in vitro and in vivo researches have demonstrated the multipotency of MSCs as a mediator of immunomodulation and a great approach for enhancement of islet engraftment. MSCs can interact with immune cells of the innate and adaptive immune systems via direct cell-cell contact or through secretomes containing numerous soluble growth and immunomodulatory factors or mitochondrial transfer. This review highlights the interactions between MSCs and different immune cells to mediate immunomodulatory functions along with the importance of MSCs therapy for the successful islet transplantation.
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Affiliation(s)
- Manju Shrestha
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Tiep Tien Nguyen
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea
| | - Jooho Park
- Department of Biomedical Chemistry, College of Biomedical & Health Science, Konkuk University, Chungju 27478, Republic of Korea
| | - Jeong Uk Choi
- College of Pharmacy, Chonnam University, Gwangju 61186, Republic of Korea
| | - Simmyung Yook
- College of Pharmacy, Keimyung University, Daegu 42601, Republic of Korea.
| | - Jee-Heon Jeong
- College of Pharmacy, Yeungnam University, Gyeongsan, Gyeongbuk 38541, Republic of Korea.
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14
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Garcia-Melchor E, Cafaro G, MacDonald L, Crowe LAN, Sood S, McLean M, Fazzi UG, McInnes IB, Akbar M, Millar NL. Novel self-amplificatory loop between T cells and tenocytes as a driver of chronicity in tendon disease. Ann Rheum Dis 2021; 80:1075-1085. [PMID: 33692018 PMCID: PMC8292554 DOI: 10.1136/annrheumdis-2020-219335] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2020] [Revised: 02/17/2021] [Accepted: 02/17/2021] [Indexed: 12/13/2022]
Abstract
OBJECTIVES Increasing evidence suggests that inflammatory mechanisms play a key role in chronic tendon disease. After observing T cell signatures in human tendinopathy, we explored the interaction between T cells and tendon stromal cells or tenocytes to define their functional contribution to tissue remodelling and inflammation amplification and hence disease perpetuation. METHODS T cells were quantified and characterised in healthy and tendinopathic tissues by flow cytometry (FACS), imaging mass cytometry (IMC) and single cell RNA-seq. Tenocyte activation induced by conditioned media from primary damaged tendon or interleukin-1β was evaluated by qPCR. The role of tenocytes in regulating T cell migration was interrogated in a standard transwell membrane system. T cell activation (cell surface markers by FACS and cytokine release by ELISA) and changes in gene expression in tenocytes (qPCR) were assessed in cocultures of T cells and explanted tenocytes. RESULTS Significant quantitative differences were observed in healthy compared with tendinopathic tissues. IMC showed T cells in close proximity to tenocytes, suggesting tenocyte-T cell interactions. On activation, tenocytes upregulated inflammatory cytokines, chemokines and adhesion molecules implicated in T cell recruitment and activation. Conditioned media from activated tenocytes induced T cell migration and coculture of tenocytes with T cells resulted in reciprocal activation of T cells. In turn, these activated T cells upregulated production of inflammatory mediators in tenocytes, while increasing the pathogenic collagen 3/collagen 1 ratio. CONCLUSIONS Interaction between T cells and tenocytes induces the expression of inflammatory cytokines/chemokines in tenocytes, alters collagen composition favouring collagen 3 and self-amplifies T cell activation via an auto-regulatory feedback loop. Selectively targeting this adaptive/stromal interface may provide novel translational strategies in the management of human tendon disorders.
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Affiliation(s)
- Emma Garcia-Melchor
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Giacomo Cafaro
- Rheumatology Unit - Department of Medicine, University of Perugia, Perugia, Italy
| | - Lucy MacDonald
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Lindsay A N Crowe
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Shatakshi Sood
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Michael McLean
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Umberto G Fazzi
- Department of Orthopaedic Surgery, Queen Elizabeth University Hospital, Glasgow, UK
| | - Iain B McInnes
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Moeed Akbar
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
| | - Neal L Millar
- Institute of Infection, Immunity and Inflammation, University of Glasgow College of Medical Veterinary and Life Sciences, Glasgow, UK
- Department of Orthopaedic Surgery, Queen Elizabeth University Hospital, Glasgow, UK
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15
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Marsh LJ, Kemble S, Reis Nisa P, Singh R, Croft AP. Fibroblast pathology in inflammatory joint disease. Immunol Rev 2021; 302:163-183. [PMID: 34096076 DOI: 10.1111/imr.12986] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 05/08/2021] [Accepted: 05/10/2021] [Indexed: 12/11/2022]
Abstract
Rheumatoid arthritis is an immune-mediated inflammatory disease in which fibroblasts contribute to both joint damage and inflammation. Fibroblasts are a major cell constituent of the lining of the joint cavity called the synovial membrane. Under resting conditions, fibroblasts have an important role in maintaining joint homeostasis, producing extracellular matrix and joint lubricants. In contrast, during joint inflammation, fibroblasts contribute to disease pathology by producing pathogenic levels of inflammatory mediators that drive the recruitment and retention of inflammatory cells within the joint. Recent advances in single-cell profiling techniques have transformed our ability to examine fibroblast biology, leading to the identification of specific fibroblast subsets, defining a previously underappreciated heterogeneity of disease-associated fibroblast populations. These studies are challenging the previously held dogma that fibroblasts are homogeneous and are providing unique insights into their role in inflammatory joint pathology. In this review, we discuss the recent advances in our understanding of how fibroblast heterogeneity contributes to joint pathology in rheumatoid arthritis. Finally, we address how these insights could lead to the development of novel therapies that directly target selective populations of fibroblasts in the future.
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Affiliation(s)
- Lucy-Jayne Marsh
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
| | - Samuel Kemble
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
| | - Patricia Reis Nisa
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
| | - Ruchir Singh
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
| | - Adam P Croft
- Rheumatology Research Group, Institute of Inflammation and Ageing (IIA), Queen Elizabeth Hospital, University of Birmingham, Birmingham, UK
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16
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Adipose-Derived Mesenchymal Stem Cells-Derived Exosomes Carry MicroRNA-671 to Alleviate Myocardial Infarction Through Inactivating the TGFBR2/Smad2 Axis. Inflammation 2021; 44:1815-1830. [PMID: 33881681 PMCID: PMC8460592 DOI: 10.1007/s10753-021-01460-9] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2021] [Revised: 03/11/2021] [Accepted: 03/29/2021] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cells (MSCs) and their derived extracellular vesicles have been reported as promising tools for the management of heart disease. The aim of this study was to explore the function of adipose-derived MSCs (adMSCs)-derived exosomes (Exo) in the progression of myocardial infarction (MI) and the molecules involved. Mouse cardiomyocytes were treated with oxygen-glucose deprivation (OGD) to mimic an MI condition in vitro. The adMSCs-derived Exo were identified and administrated into the OGD-treated cardiomyocytes, and then the viability and apoptosis of cells, and the secretion of fibrosis- and inflammation-related cytokines in cells were determined. Differentially expressed microRNAs (miRNAs) in cells after Exo treatment were screened using a microarray analysis. The downstream molecules regulated by miR-671 were explored through bioinformatic analysis. Involvements of miR-671 and transforming growth factor beta receptor 2 (TGFBR2) in the exosome-mediated events were confirmed by rescue experiments. A murine model with MI was induced and treated with Exo for functional experiments in vivo. Compared to phosphate-buffered saline treatment, the Exo treatment significantly enhanced viability while reduced apoptosis of cardiomyocytes, and in reduced myocardial fibrosis and inflammation both in vitro and in vivo. miR-671 was significantly upregulated in cells after Exo treatment. Downregulation of miR-671 blocked the protective functions of Exo. miR-671 targeted TGFBR2 and suppressed phosphorylation of Smad2. Artificial downregulation of TGFBR2 enhanced viability of the OGD-treated cardiomyocytes. This study suggested that adMSC-derived exosomal miR-671 directly targets TGFBR2 and reduces Smad2 phosphorylation to alleviate MI-like symptoms both in vivo and in vitro.
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17
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González-González A, García-Sánchez D, Dotta M, Rodríguez-Rey JC, Pérez-Campo FM. Mesenchymal stem cells secretome: The cornerstone of cell-free regenerative medicine. World J Stem Cells 2020; 12:1529-1552. [PMID: 33505599 PMCID: PMC7789121 DOI: 10.4252/wjsc.v12.i12.1529] [Citation(s) in RCA: 90] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2020] [Revised: 10/07/2020] [Accepted: 11/11/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are the most frequently used stem cells in clinical trials due to their easy isolation from various adult tissues, their ability of homing to injury sites and their potential to differentiate into multiple cell types. However, the realization that the beneficial effect of MSCs relies mainly on their paracrine action, rather than on their engraftment in the recipient tissue and subsequent differentiation, has opened the way to cell-free therapeutic strategies in regenerative medicine. All the soluble factors and vesicles secreted by MSCs are commonly known as secretome. MSCs secretome has a key role in cell-to-cell communication and has been proven to be an active mediator of immune-modulation and regeneration both in vitro and in vivo. Moreover, the use of secretome has key advantages over cell-based therapies, such as a lower immunogenicity and easy production, handling and storage. Importantly, MSCs can be modulated to alter their secretome composition to better suit specific therapeutic goals, thus, opening a large number of possibilities. Altogether these advantages now place MSCs secretome at the center of an important number of investigations in different clinical contexts, enabling rapid scientific progress in this field.
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Affiliation(s)
- Alberto González-González
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Daniel García-Sánchez
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Monica Dotta
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - José C Rodríguez-Rey
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain
| | - Flor M Pérez-Campo
- Department of Molecular Biology_IDIVAL, Faculty of Medicine, University of Cantabria, Santander 39011, Cantabria, Spain.
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18
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Ringdén O, Gustafsson B, Sadeghi B. Mesenchymal Stromal Cells in Pediatric Hematopoietic Cell Transplantation a Review and a Pilot Study in Children Treated With Decidua Stromal Cells for Acute Graft-versus-Host Disease. Front Immunol 2020; 11:567210. [PMID: 33193339 PMCID: PMC7604265 DOI: 10.3389/fimmu.2020.567210] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 09/02/2020] [Indexed: 12/14/2022] Open
Abstract
Mesenchymal stromal cells (MSCs) are rare precursors in all organs of the body. MSCs have profound anti-inflammatory effects and reduce alloreactivity in vitro and in vivo. In pediatric allogeneic hematopoietic cell transplantation (HCT), MSCs have mainly been used to treat acute graft-versus-host disease (GVHD). MSCs are commercially available for this indication in Canada, Japan, and New Zeeland. More rare indications for MSCs in pediatric patients include graft failure and chronic GVHD. MSCs from bone marrow, adipose tissue, umbilical cord, Wharton's jelly, placenta tissue, and decidua have been used, but the optimal clinical stromal cell source has not been compared in clinical trials. More experimental clinical indications using MSCs, such as sepsis, acute respiratory distress syndrome, hemorrhages, pneumo-mediastinum, and neuroinflammation have primarily been explored in animal models or adult HCT patients. MSCs have almost no if any side-effects. In this pilot study we report the outcome of six children treated with decidua stromal cells (DSCs) for steroid refractory acute GVHD. At 6 months, complete response was seen in four patients and partial response in two patients. One child with high-risk ALL died from relapse and a boy with sickle cell disease died from a cerebral hemorrhage. Five-year survival was 67% and all survivors showed a Lansky score of 100%. To conclude, MSCs from various organs are well-tolerated and have shown an encouraging outcome for acute GVHD in pediatric patients.
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Affiliation(s)
- Olle Ringdén
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
| | - Britt Gustafsson
- Division of Pediatrics, CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Behnam Sadeghi
- Translational Cell Therapy Research (TCR), Division of Pediatrics, Department of Clinical Science, Intervention and Technology (CLINTEC), Karolinska Institutet, Stockholm, Sweden
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Kaul NC, Mohapatra SR, Adam I, Tucher C, Tretter T, Opitz CA, Lorenz HM, Tykocinski LO. Hypoxia decreases the T helper cell-suppressive capacity of synovial fibroblasts by downregulating IDO1-mediated tryptophan metabolism. Rheumatology (Oxford) 2020; 59:1148-1158. [PMID: 31846032 DOI: 10.1093/rheumatology/kez587] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Revised: 10/07/2019] [Indexed: 11/14/2022] Open
Abstract
OBJECTIVE The development of RA is linked to local infiltration of immune cells and to changes in the phenotype of synovial fibroblasts. Synovial fibroblasts possess the capacity to suppress T cell responses through indoleamine 2, 3-dioxygenase 1 (IDO1)-mediated tryptophan metabolism. However, synovial fibroblasts from RA patients are restricted in this immune-modulatory function. Moreover, hypoxic conditions are detected within synovial tissues of RA patients, with oxygen tensions of only 3.2% O2. This study aims at investigating the effects of hypoxia on the interaction between T cells and synovial fibroblasts, particularly on the T cell-suppressive capacities of synovial fibroblasts. METHODS Synovial fibroblasts were cultured with Th cells under normoxic and hypoxic conditions (3% O2). Th cell proliferation was detected by flow cytometry. Tryptophan and kynurenine amounts were measured by HPLC. IDO1 expression and signal transducer and activator of transcription 1 (STAT1) phosphorylation were quantified by real-time PCR or western blot, and cytokine secretion by ELISA. RESULTS Hypoxic conditions strongly diminished the Th cell-suppressive capacities of both OA synovial fibroblasts and RA synovial fibroblasts. Accordingly, IDO1 mRNA and protein expression, STAT1 phosphorylation and tryptophan metabolism were greatly reduced in OA synovial fibroblasts by hypoxia. MMP-3, IL-6, IL-10 and IFNγ secretion were significantly decreased under hypoxia in synovial fibroblast-Th cell co-cultures, while IL-17A levels were elevated. Supplementation with IFNγ, a well-known inducer of IDO1 expression, could rescue neither IDO1 expression nor Th cell suppression under hypoxic conditions. CONCLUSION Hypoxia strongly affected the crosstalk between synovial fibroblasts and Th cells. By reducing the efficiency of synovial fibroblasts to restrict Th cell proliferation and by increasing the expression of IL-17A, hypoxia might have implications on the pathophysiology of RA.
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Affiliation(s)
- Nathalie-Christin Kaul
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Soumya R Mohapatra
- Brain Cancer Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Isabell Adam
- Brain Cancer Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christine Tucher
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Theresa Tretter
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Christiane A Opitz
- Brain Cancer Metabolism, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Hanns-Martin Lorenz
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
| | - Lars-Oliver Tykocinski
- Division of Rheumatology, Department of Internal Medicine V, Heidelberg University Hospital
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20
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Miranda VHS, Gomes TR, Eller DE, Ferraz LDCN, Chaves AT, Bicalho KA, Silva CEC, Birbrair A, Pascoal Xavier MA, de Goes AM, Corrêa-Oliveira R, Alves ÉAR, Bozzi A. Liver damage in schistosomiasis is reduced by adipose tissue-derived stem cell therapy after praziquantel treatment. PLoS Negl Trop Dis 2020; 14:e0008635. [PMID: 32853206 PMCID: PMC7480869 DOI: 10.1371/journal.pntd.0008635] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Revised: 09/09/2020] [Accepted: 07/23/2020] [Indexed: 12/19/2022] Open
Abstract
Background In view of the potential immunosuppressive and regenerative properties of mesenchymal stem cells (MSC), we investigated whether transplantation of adipose tissue-derived stem cells (ASC) could be used to control the granulomatous reaction in the liver of mice infected with Schistosoma mansoni after Praziquantel (PZQ) treatment. Methodology/Prinicpal findings C57BL/6 mice infected with S. mansoni were treated with PZQ and transplanted intravenously with ASC from uninfected mice. Liver morpho-physiological and immunological analyses were performed. The combined PZQ/ASC therapy significantly reduced the volume of hepatic granulomas, as well as liver damage as measured by ALT levels. We also observed that ASC accelerated the progression of the granulomatous inflammation to the advanced/curative phase. The faster healing interfered with the expression of CD28 and CTLA-4 molecules in CD4+ T lymphocytes, and the levels of IL-10 and IL-17 cytokines, mainly in the livers of PZQ/ASC-treated mice. Conclusions Our results show that ASC therapy after PZQ treatment results in smaller granulomas with little tissue damage, suggesting the potential of ASC for the development of novel therapeutic approaches to minimize hepatic lesions as well as a granulomatous reaction following S. mansoni infection. Further studies using the chronic model of schistosomiasis are required to corroborate the therapeutic use of ASC for schistosomiasis. Schistosomiasis is the second most prevalent parasitic disease in the world and is caused by the Schistosoma trematode. This disease is characterized by a granulomatous reaction around parasite eggs trapped in the tissues. The liver is one of the most affected organs and can develop severe fibrosis. Praziquantel (PZQ) is the treatment for schistosomiasis and kills the adult the worm; however, inflammation still persists around the eggs in the tissues. Mesenchymal stem cells (MSC) have been extensively studied as an alternative therapy to repair tissues and to stop inflammation due to their potential to differentiate in several cells types (bone, cartilage, fat, tendon, muscle, and marrow stroma), and to interfere with immune responses. This scenario has motivated the authors to investigate the use of MSC extract from adipose tissue (ASC) associated with PZQ to treat schistosomiasis. Briefly, mice were treated with PZQ followed by ASC injection showing significant reduction of the granulomas and normal levels of the enzyme alanine aminotransferase, an indicator of liver damage. These results suggest that ASC has the potential to be used as a novel therapeutic approach to control inflammation following infection by S. mansoni or liver disorders. Although the findings are promising, further studies using the chronic model of schistosomiasis are required to confirm using ASC for schistosomiasis therapy.
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Affiliation(s)
| | - Talita Rocha Gomes
- Instituto René Rachou, Fiocruz Minas, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Morfologia, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | | | | | | | | | | | - Alexander Birbrair
- Departamento de Patologia, ICB, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Marcelo Antônio Pascoal Xavier
- Instituto René Rachou, Fiocruz Minas, Belo Horizonte, Minas Gerais, Brazil
- Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | | | | | | | - Adriana Bozzi
- Instituto René Rachou, Fiocruz Minas, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Ciências Biológicas, Universidade Estadual de Santa Cruz, Ilhéus, Bahia, Brazil
- * E-mail:
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Gomzikova MO, Kletukhina SK, Kurbangaleeva SV, Neustroeva OA, Vasileva OS, Garanina EE, Khaiboullina SF, Rizvanov AA. Mesenchymal Stem Cell Derived Biocompatible Membrane Vesicles Demonstrate Immunomodulatory Activity Inhibiting Activation and proliferation of Human Mononuclear Cells. Pharmaceutics 2020; 12:pharmaceutics12060577. [PMID: 32585863 PMCID: PMC7356506 DOI: 10.3390/pharmaceutics12060577] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Revised: 06/15/2020] [Accepted: 06/18/2020] [Indexed: 01/27/2023] Open
Abstract
Immune-mediated diseases are characterized by abnormal activity of the immune system. The cytochalasin B-induced membrane vesicles (CIMVs) are innovative therapeutic instruments. However, the immunomodulating activity of human mesenchymal stem cell (MSC)-derived CIMVs (CIMVs-MSCs) remains unknown. Therefore, we sought to investigate the immunological properties of CIMVs-MSCs and evaluate their effect on human peripheral blood mononuclear cells (PBMCs). We found that CIMVs-MSCs are primarily uptaken by monocytes and B-cells. Additionally, we demonstrated that CIMVs-MSCs inhibit phytohemagglutinin (PHA)-induced proliferation of PBMCs, with more pronounced effect on T-lymphocytes expansion as compared to that of B-cells. In addition, activation of T-helpers (CD4+CD25+), B-cells (CD19+CD25+), and T-cytotoxic lymphocytes (CD8+CD25+) was also significantly suppressed by CIMVs-MSCs. Additionally, CIMVs-MSCs decreased secretion of epidermal growth factor (EGF) and pro-inflammatory Fractalkine in a population of PBMCs, while the releases of FGF-2, G-CSF, anti-inflammatory GM-CSF, MCP-3, anti-inflammatory MDC, anti-inflammatory IL-12p70, pro-inflammatory IL-1b, and MCP-1 were increased. We analyzed the effect of CIMVs-MSCs on an isolated population of CD4+ and CD8+ T-lymphocytes and demonstrated their different immune response and cytokine secretion. Finally, we observed that no xenogeneic nor allogeneic transplantation of CIMVs induced an immune response in mice. Our data suggest that CIMVs-MSCs have immunosuppressive properties, are potential agents for immunomodulating treatment, and are worthy of further investigation.
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Affiliation(s)
- Marina O. Gomzikova
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
- M.M. Shemyakin–Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
- Correspondence: ; Tel.: +7-9178572269
| | - Sevindzh K. Kletukhina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
| | - Sirina V. Kurbangaleeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
| | - Olga A. Neustroeva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
| | - Olga S. Vasileva
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
| | - Ekaterina E. Garanina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
| | - Svetlana F. Khaiboullina
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
- Department of Microbiology and Immunology, University of Nevada, Reno School of Medicine, Reno, NV 89557, USA
| | - Albert A. Rizvanov
- Institute of Fundamental Medicine and Biology, Kazan Federal University, Kazan 420008, Russia; (S.K.K.); (S.V.K.); (O.A.N.); (O.S.V.); (E.E.G.); (S.F.K.); (A.A.R.)
- M.M. Shemyakin–Yu.A. Ovchinnikov Institute of Bioorganic Chemistry of the Russian Academy of Sciences, Moscow 117997, Russia
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22
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Caffi V, Espinosa G, Gajardo G, Morales N, Durán MC, Uberti B, Morán G, Plaza A, Henríquez C. Pre-conditioning of Equine Bone Marrow-Derived Mesenchymal Stromal Cells Increases Their Immunomodulatory Capacity. Front Vet Sci 2020; 7:318. [PMID: 32656251 PMCID: PMC7325884 DOI: 10.3389/fvets.2020.00318] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 05/11/2020] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are increasingly explored for the treatment of degenerative and inflammatory diseases in human and veterinary medicine. One of the key characteristics of MSCs is that they modulate inflammation mainly through the secretion of soluble mediators. However, despite widespread clinical use, knowledge regarding the effector mechanisms of equine MSCs, and consequently their effectiveness in the treatment of diseases, is still unknown. The objectives of this study were to determine the mechanisms underlying inhibition of lymphocyte proliferation by equine bone marrow-derived MSCs, and to evaluate the effect of pre-conditioning of equine MSCs with different pro-inflammatory cytokines on inhibition of lymphocyte proliferation. We determined that inhibition of lymphocyte proliferation by equine MSCs depends on activity of prostaglandin-endoperoxide synthase 2 and indoleamine 2,3-dioxygenase. Additionally, pre-conditioning of MSCs with TNF-α, IFN-γ or their combination significantly increased the expression of prostaglandin-endoperoxide synthase 2, indoleamine 2,3-dioxygenase, iNOS and IL-6. This upregulation correlated with an increased inhibitory effect of MSCs on lymphocyte proliferation. In conclusion, pre-conditioning of bone marrow-derived MSC increases their inhibitory effect on lymphocyte proliferation in horses.
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Affiliation(s)
- Valeria Caffi
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile.,Escuela de Graduados, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Gabriel Espinosa
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Gonzalo Gajardo
- Escuela de Graduados, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Natalia Morales
- Escuela de Graduados, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - María Carolina Durán
- Instituto de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Benjamín Uberti
- Instituto de Ciencias Clínicas, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Gabriel Morán
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
| | - Anita Plaza
- Instituto de Medicina, Facultad de Medicina, Universidad Austral de Chile, Valdivia, Chile
| | - Claudio Henríquez
- Instituto de Farmacología y Morfofisiología, Facultad de Ciencias Veterinarias, Universidad Austral de Chile, Valdivia, Chile
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23
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Thomson CA, Nibbs RJ, McCoy KD, Mowat AM. Immunological roles of intestinal mesenchymal cells. Immunology 2020; 160:313-324. [PMID: 32181492 DOI: 10.1111/imm.13191] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2020] [Revised: 03/09/2020] [Accepted: 03/10/2020] [Indexed: 12/20/2022] Open
Abstract
The intestine is continuously exposed to an enormous variety and quantity of antigens and innate immune stimuli derived from both pathogens and harmless materials, such as food and commensal bacteria. Accordingly, the intestinal immune system is uniquely adapted to ensure appropriate responses to the different kinds of challenge; maintaining tolerance to harmless antigens in the steady-state, whilst remaining poised to deal with potential pathogens. To accomplish this, leucocytes of the intestinal immune system have to adapt to a constantly changing environment and interact with many different non-leucocytic intestinal cell types, including epithelial and endothelial cells, neurons, and a heterogenous network of intestinal mesenchymal cells (iMC). These interactions are intricately involved in the generation of protective immunity, the elaboration of inflammatory responses, and the development of inflammatory conditions, such as inflammatory bowel diseases. Here we discuss recent insights into the immunological functions of iMC under homeostatic and inflammatory conditions, focusing particularly on iMC in the mucosa and submucosa, and highlighting how an appreciation of the immunology of iMC may help understand the pathogenesis and treatment of disease.
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Affiliation(s)
- Carolyn A Thomson
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Robert J Nibbs
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Allan Mcl Mowat
- Institute of Infection, Immunity and Inflammation, College of Medicine, Veterinary Medicine and Life Sciences, University of Glasgow, Glasgow, UK
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24
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Meese S, Ulbrich SE, Bollwein H, Bruckmaier R, Wellnitz O, Kreuzer M, Röntgen M, Gimsa U, Schwarm A. Methane emission, metabolism, and performance of Holstein dairy cows with low, medium, and high lymphocyte proliferation during transition. J Dairy Sci 2020; 103:4367-4377. [PMID: 32147260 DOI: 10.3168/jds.2019-17584] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2019] [Accepted: 01/02/2020] [Indexed: 11/19/2022]
Abstract
This study aimed to identify interactions between state of lactation (dry or early lactating) and immune responder group (low, medium, or high) for energy metabolism traits as well as metabolic and immunological traits in dairy cows. In early lactation, when the energy priority of cows shifts toward the mammary gland, the energy available to be partitioned toward the immune system may differ among individuals. The equilibrium between energy supply from feed, digestion, and body reserve mobilization and energy expenditure with milk, immune system, methane, and heat production is delicate in this stage. Seventeen Holstein cows entering their second to fifth lactation were kept under comparable feeding, housing, and management conditions and were studied from 14 ± 6 d before calving to 11 ± 3 d after calving. Feed intake, milk yield, body condition, blood metabolites, and cortisol as well as gaseous exchange in respiration chambers were measured. The latter was used to quantify methane emission and to calculate resting metabolic rate and heat production. Subsets of blood leukocytes and peripheral blood mononuclear cells (PBMC) were monitored. Activation and proliferation of the PBMC in response to the mitogen phytohemagglutinin ante- and postpartum were assessed using the oxygen consumption rate (24-h cell culture assay) and the 3-(4,5-dimethylthiazol-2-yl)-2,5 diphenyl tetrazolium bromide (MTT) assay (72-h cell culture assay). Cows were classified based on the in vitro proliferative response of the PBMC measured postpartum in low (n = 6), medium (n = 5), and high (n = 6) responders. We found no interaction of state of lactation with responder group for feed intake, milk yield, efficiency, metabolic traits, and immune cell activation ante- and postpartum. However, after calving, low-responder cows produced less methane per unit of body weight and per unit of energy-corrected milk compared with the other cows. This might be indicative of a low rumen fermentation intensity. Low responders might therefore suffer from a lower availability of digestible energy in early lactation and not be able to sustain the shift from immune cell activation to proliferation. If so, the selection of environmentally friendly low-methane emitters could promote phenotypes with a compromised immune response in the critical early lactation.
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Affiliation(s)
- S Meese
- ETH Zurich, Animal Nutrition, Institute of Agricultural Sciences, 8092 Zurich, Switzerland; AgroVet-Strickhof, 8315 Lindau, Switzerland
| | - S E Ulbrich
- ETH Zurich, Animal Physiology, Institute of Agricultural Sciences, 8092 Zurich, Switzerland
| | - H Bollwein
- Clinic of Reproductive Medicine, Vetsuisse Faculty, University of Zurich, 8057 Zurich, Switzerland
| | - R Bruckmaier
- Veterinary Physiology, Vetsuisse Faculty, University of Berne, 3001 Berne, Switzerland
| | - O Wellnitz
- Veterinary Physiology, Vetsuisse Faculty, University of Berne, 3001 Berne, Switzerland
| | - M Kreuzer
- ETH Zurich, Animal Nutrition, Institute of Agricultural Sciences, 8092 Zurich, Switzerland
| | - M Röntgen
- Institute of Muscle Biology and Growth, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany
| | - U Gimsa
- Institute of Behavioural Physiology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany
| | - A Schwarm
- ETH Zurich, Animal Nutrition, Institute of Agricultural Sciences, 8092 Zurich, Switzerland; Department of Animal and Aquacultural Sciences, Norwegian University of Life Sciences, 1432 Ås, Norway.
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25
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Petrasca A, Phelan JJ, Ansboro S, Veale DJ, Fearon U, Fletcher JM. Targeting bioenergetics prevents CD4 T cell–mediated activation of synovial fibroblasts in rheumatoid arthritis. Rheumatology (Oxford) 2020; 59:2816-2828. [DOI: 10.1093/rheumatology/kez682] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2019] [Revised: 12/16/2019] [Indexed: 02/07/2023] Open
Abstract
Abstract
Objectives
We investigated the reciprocal relationship linking fibroblast-like synoviocytes (FLS) and T lymphocytes in the inflamed RA synovium and subsequently targeted cellular metabolic pathways in FLS to identify key molecular players in joint inflammation.
Methods
RA FLS were cultured with CD4 T cells or T cell conditioned medium (CD4CM); proliferation, expression of adhesion molecules and intracellular cytokines were examined by flow cytometry. FLS invasiveness and secreted cytokines were measured by transwell matrigel invasion chambers and ELISA, while metabolic profiles were determined by extracellular Seahorse flux analysis. Gene expression was quantified by real-time quantitative RT-PCR.
Results
Our results showed mutual activation between CD4 T cells and FLS, which resulted in increased proliferation and expression of intercellular adhesion molecule 1 and vascular cell adhesion molecule 1 by both CD4 T cells and FLS. Furthermore, interaction between CD4 T cells and FLS resulted in an increased frequency of TNF-α+, IFN-γ+ and IL-17A+ CD4 T cells and augmented TNF-α, IFN-γ, IL-17A, IL-6, IL-8 and VEGF secretion. Moreover, CD4CM promoted invasiveness and boosted glycolysis in FLS while downregulating oxidative phosphorylation, effects paralleled by increased glucose transporters GLUT1 and GLUT3; key glycolytic enzymes GSK3A, HK2, LDHA and PFKFB3; angiogenic factor VEGF and MMP-3 and MMP-9. Importantly, these effects were reversed by the glycolytic inhibitor 2-DG and AMP analogue 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR).
Conclusion
This study demonstrates that CD4 T cells elicit an aggressive phenotype in FLS, which subsequently upregulate glycolysis to meet the increased metabolic demand. Accordingly, 2-DG and AICAR prevent this activation, suggesting that glycolytic manipulation could have clinical implications for RA treatment.
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Affiliation(s)
- Andreea Petrasca
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - James J Phelan
- School of Medicine, Trinity Translational Medicine Institute, Trinity College Dublin, Dublin, Ireland
| | - Sharon Ansboro
- Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
| | - Douglas J Veale
- Eular Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin, Ireland
| | - Ursula Fearon
- Molecular Rheumatology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Eular Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin, Ireland
| | - Jean M Fletcher
- School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
- Eular Centre for Arthritis and Rheumatic Diseases, St. Vincent’s University Hospital, Dublin, Ireland
- School of Medicine, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland
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26
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Liu C, Sun J. Osteogenically differentiated mesenchymal stem cells induced by hydrolyzed fish collagen maintain their immunomodulatory effects. Life Sci 2019; 238:116970. [PMID: 31639395 DOI: 10.1016/j.lfs.2019.116970] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 09/25/2019] [Accepted: 10/14/2019] [Indexed: 01/14/2023]
Abstract
AIMS The reciprocity between stem cells and biomaterials is an essential topic in bone tissue engineering. Bone marrow mesenchymal stromal cells (BMSCs) have attracted considerable attention in regenerative medicine owing to their ability to self-renew and differentiate into osteoblasts, and more importantly, their immunomodulatory effects on the immune response. Ideal biomaterials should be osteo-inductive, environmentally sustainable, and economical. Our previous study showed that hydrolyzed fish collagen (HFC) can meet each of the above requirements. However, it is still unclear whether BMSCs maintain their immunomodulatory properties after osteogenic differentiation induced by HFC. MAIN METHODS Non-commercial sources of BMSCs were isolated from Sprague-Dawley (SD) rats. Osteogenically differentiated BMSCs induced by HFC and undifferentiated BMSCs were co-cultured with PBMC or NR 8383 macrophages, respectively. Cell proliferation of PBMC was examined using a BrdU uptake assay. In addition, the IL-6, TGF-β1, IL-10, PGE2, and nitric oxide levels were determined. The expressions of TSG-6 (TNF-stimulated gene 6) and IDO (indoleamine 2, 3-dioxygenase) genes were analyzed using qRT-PCR. KEY FINDINGS The results revealed that HFC-induced BMSCs suppressed the proliferation of PBMC. The expression levels of anti-inflammatory mediators including IL-6, TGF-β1, and PGE2 significantly increased after 48 h of co-culture. Moreover, the nitric oxide production increased during osteogenesis induced by HFC, whereas the level of TSG-6 and IDO remained unchanged after osteogenic differentiation. HFC-BMSCs inhibited the inflammatory mediator production (IL-1β, TNF-α) in LPS-stimulated macrophages. SIGNIFICANCE Taken together, these findings suggest that the immunomodulation ability is still retained in osteogenically differentiated BMSCs induced by HFC.
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Affiliation(s)
- Chao Liu
- Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Biomaterials Research and Testing Center, Shanghai, 200023, China
| | - Jiao Sun
- Shanghai Ninth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai Biomaterials Research and Testing Center, Shanghai, 200023, China.
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27
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Li F, Tang Y, Song B, Yu M, Li Q, Zhang C, Hou J, Yang R. Nomenclature clarification: synovial fibroblasts and synovial mesenchymal stem cells. Stem Cell Res Ther 2019; 10:260. [PMID: 31426847 PMCID: PMC6701095 DOI: 10.1186/s13287-019-1359-x] [Citation(s) in RCA: 56] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
Synovial-derived cells, found in the synovial membrane of human joints, were obtained by digestion of the synovial membrane and were subsequently expanded in vitro. The identity of synovial-derived cells has long been a topic of debate. The terms "type B synoviocytes," "fibroblast-like synoviocytes (FLS)," "synovium-derived mesenchymal stem cells (MSCs)," and "synovial fibroblasts (SF)" appeared in different articles related to human synovial-derived cells in various disease models, yet they seemed to be describing the same cell type. However, to date, there is no clear standard to distinguish these terms; thus, the hypothesis that they represent the same cell type is currently inconclusive. Therefore, this review aims to clarify the similarities and differences between these terms and to diffuse the chaotic nomenclature of synovial-derived cells.
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Affiliation(s)
- Fangqi Li
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China
| | - Yiyong Tang
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China
| | - Bin Song
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China
| | - Menglei Yu
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China
| | - Qingyue Li
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China
| | - Congda Zhang
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China
| | - Jingyi Hou
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China.
| | - Rui Yang
- Department of Orthopedic, Sun Yat-sen Memorial Hospital Sun Yat-sen University, NO.107 Yan Jiang West Road, Guangzhou, Guangdong Province, 510120, China.
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Emerging Role of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Pathogenesis of Haematological Malignancies. Stem Cells Int 2019; 2019:6854080. [PMID: 31281380 PMCID: PMC6589251 DOI: 10.1155/2019/6854080] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2018] [Accepted: 03/11/2019] [Indexed: 02/07/2023] Open
Abstract
Homoeostasis of bone marrow microenvironment depends on a precise balance between cell proliferation and death, which is supported by the cellular-extracellular matrix crosstalk. Multipotent mesenchymal stromal cells (MSC) are the key elements to provide the specialized bone marrow microenvironment by supporting, maintaining, and regulating the functions and fate of haematopoietic stem cells. Despite the great potential of MSC for cell therapy in several diseases due to their regenerative, immunomodulatory, and anti-inflammatory properties, they can also contribute to modulate tumor microenvironment. The extracellular vesicles that comprise exosomes and microvesicles are important mediators of intercellular communication due to their ability to change phenotype and physiology of different cell types. These vesicles may interact not only with neighbouring cells but also with cells from distant tissues to either maintain tissue homoeostasis or participate in disease pathogenesis. This review focuses on the current knowledge about the physiological role of MSC-extracellular vesicles, as well as their deregulation in haematological malignancies and their potential applications as biomarkers for diagnosis, progression, and treatment monitoring of such diseases.
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29
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Qin Y, Lee Y, Seo J, Kim T, Shin JH, Park SH. NIH3T3 Directs Memory-Fated CTL Programming and Represses High Expression of PD-1 on Antitumor CTLs. Front Immunol 2019; 10:761. [PMID: 31031760 PMCID: PMC6470252 DOI: 10.3389/fimmu.2019.00761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Accepted: 03/21/2019] [Indexed: 11/15/2022] Open
Abstract
Memory CD8+ T cells have long been considered a promising population for adoptive cell therapy (ACT) due to their long-term persistence and robust re-stimulatory response. NIH3T3 is an immortalized mouse embryonic fibroblast cell line. We report that NIH3T3-conditioned medium (CM) can augment effector functions of CTLs following antigen priming and confer phenotypic and transcriptional properties of central memory cells. After NIH3T3-CM-educated CTLs were infused into naïve mice, they predominantly developed to central memory cells. A large number of NIH3T3-CM-educated CTLs with high functionality persisted and infiltrated to tumor mass. In addition, NIH3T3-CM inhibited CTLs expression of PD-1 in vitro and repressed their high expression of PD-1 in tumor microenvironment after adoptive transfer. Consequently, established tumor models showed that infusion of NIH3T3-CM-educated CTLs dramatically improved CTL mediated-antitumor immunity. Furthermore, NIH3T3-CM also promoted human CD8+ T cells differentiation into memory cells. These results suggest that NIH3T3-CM-programmed CTLs are good candidates for adoptive transfer in tumor therapy.
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Affiliation(s)
- Yingyu Qin
- Department of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
| | - Yuna Lee
- ImmunoMax Co., Ltd, Korea University, Seoul, South Korea
| | - Jaeho Seo
- ImmunoMax Co., Ltd, Korea University, Seoul, South Korea
| | - Taehyun Kim
- ImmunoMax Co., Ltd, Korea University, Seoul, South Korea
| | - Jung Hoon Shin
- ImmunoMax Co., Ltd, Korea University, Seoul, South Korea
| | - Se-Ho Park
- Department of Life Sciences and Biotechnology, Korea University, Seoul, South Korea
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30
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The mesenchymal stem cell secretome as an acellular regenerative therapy for liver disease. J Gastroenterol 2019; 54:763-773. [PMID: 31270691 PMCID: PMC6698261 DOI: 10.1007/s00535-019-01599-1] [Citation(s) in RCA: 112] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Accepted: 06/11/2019] [Indexed: 02/04/2023]
Abstract
The use of mesenchymal stem cells (MSC) for tissue repair has garnered much interest and has been evaluated in several disease settings. Recent evidence indicates that the beneficial effects observed with MSC-based therapy can be mediated through the paracrine release of extracellular vesicles and other soluble proteins or biologically active molecules, which collectively constitute the MSC secretome. In this concise overview, we highlight results from preclinical and other studies that demonstrate the therapeutic efficacy of the MSC secretome for diseases that are characterized by liver injury or fibrosis. The potential for the use of the MSC secretome as an acellular regenerative therapy and approaches for the isolation of a secretome product for therapeutic applications are highlighted. The use of the MSC secretome as an acellular therapeutic agent could provide several advantages over the use of cell-based therapies for liver diseases.
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31
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He JG, Xie QL, Li BB, Zhou L, Yan D. Exosomes Derived from IDO1-Overexpressing Rat Bone Marrow Mesenchymal Stem Cells Promote Immunotolerance of Cardiac Allografts. Cell Transplant 2018; 27:1657-1683. [PMID: 30311501 PMCID: PMC6299201 DOI: 10.1177/0963689718805375] [Citation(s) in RCA: 52] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2018] [Revised: 09/10/2018] [Accepted: 09/11/2018] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The immunosuppressive activity of mesenchymal stem cells (MSCs) has been exploited to induce tolerance after organ transplantation. The indoleamine 2,3-dioxygenase (IDO) may have beneficial effects in the immunoregulatory properties of MSCs. It was recently revealed that exosomes derived from MSCs play important roles in mediating the biological functions of MSCs. This study aimed to explore the roles of exosomes derived from MSCs in the induction of immune tolerance. METHODS Dendritic cells (DCs) and T-cells were cultured with exosomes derived from rat bone marrow MSCs (BMSCs) overexpressing IDO1 or controls. For the in-vivo study, rats received heart transplants and were treated with exosomes from IDO-BMSCs and heart function was evaluated. Flow cytometry was used to detect expression of cell surface markers. Cytokine levels were detected in culture supernatants or serum samples. Protein and microRNA expressions in exosomes were investigated by chips. RESULTS Exosomes from IDO-BMSCs cultured with DCs and T-cells (1) downregulated CD40, CD86, CD80, MHC-II, CD45RA, CD45RA+CD45RB, OX62, and upregulated CD274 expression, (2) increased the number of regulatory T-cells (Tregs) and decreased the number of CD8+ T-cells, and (3) decreased the levels of pro-inflammatory cytokines, but increased the levels of anti-inflammatory cytokines compared with the other groups. Transplanted rats, which were injected with exosomes from IDO-BMSCs, had reduced allograft-targeting immune responses and improved cardiac allograft function. Exosomes secreted by IDO-BMSCs exhibited significant upregulations of the immunoregulatory protein FHL-1, miR-540-3p, and a downregulation of miR-338-5p. CONCLUSION Exosomes derived from IDO-BMSCs can be used to promote immunotolerance and prolong the survival of cardiac allografts.
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Affiliation(s)
- Ji-Gang He
- Department of Cardiovascular Surgery, First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Qiao-Li Xie
- Department of Cardiovascular Surgery, First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Bei-Bei Li
- Department of Cardiovascular Surgery, First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Liang Zhou
- Department of Cardiology, First People’s Hospital of Yunnan Province, Kunming, Yunnan Province, China
| | - Dan Yan
- Department of Intensive Care Unit, First People’s Hospital of Yunnan Province, Yunnan Province, China
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32
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Gaber T, Schönbeck K, Hoff H, Tran CL, Strehl C, Lang A, Ohrndorf S, Pfeiffenberger M, Röhner E, Matziolis G, Burmester GR, Buttgereit F, Hoff P. CTLA-4 Mediates Inhibitory Function of Mesenchymal Stem/Stromal Cells. Int J Mol Sci 2018; 19:ijms19082312. [PMID: 30087255 PMCID: PMC6121442 DOI: 10.3390/ijms19082312] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2018] [Revised: 08/01/2018] [Accepted: 08/02/2018] [Indexed: 02/07/2023] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are stem cells of the connective tissue, possess a plastic phenotype, and are able to differentiate into various tissues. Besides their role in tissue regeneration, MSCs perform additional functions as a modulator or inhibitor of immune responses. Due to their pleiotropic function, MSCs have also gained therapeutic importance for the treatment of autoimmune diseases and for improving fracture healing and cartilage regeneration. However, the therapeutic/immunomodulatory mode of action of MSCs is largely unknown. Here, we describe that MSCs express the inhibitory receptor CTLA-4 (cytotoxic T lymphocyte antigen 4). We show that depending on the environmental conditions, MSCs express different isoforms of CTLA-4 with the secreted isoform (sCTLA-4) being the most abundant under hypoxic conditions. Furthermore, we demonstrate that the immunosuppressive function of MSCs is mediated mainly by the secretion of CTLA-4. These findings open new ways for treatment when tissue regeneration/fracture healing is difficult.
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Affiliation(s)
- Timo Gaber
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Kerstin Schönbeck
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Holger Hoff
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Cam Loan Tran
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Cindy Strehl
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Annemarie Lang
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Sarah Ohrndorf
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
| | - Moritz Pfeiffenberger
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Eric Röhner
- Department of Orthopedics, Campus Eisenberg, Jena University Hospital, Klosterlausnitzer Straße 81, 07607 Eisenberg, Germany.
| | - Georg Matziolis
- Department of Orthopedics, Campus Eisenberg, Jena University Hospital, Klosterlausnitzer Straße 81, 07607 Eisenberg, Germany.
| | - Gerd-R Burmester
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Frank Buttgereit
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
| | - Paula Hoff
- Department of Rheumatology and Clinical Immunology, Charité⁻Universitätsmedizin Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, 10117 Berlin, Germany.
- German Rheumatism Research Centre (DRFZ) Berlin, A Leibniz Institute, 10117 Berlin, Germany.
- Department of Orthopedics, Campus Eisenberg, Jena University Hospital, Klosterlausnitzer Straße 81, 07607 Eisenberg, Germany.
- Endokrinologikum Berlin, 10117 Berlin, Germany.
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Generation and Applications of Induced Pluripotent Stem Cell-Derived Mesenchymal Stem Cells. Stem Cells Int 2018; 2018:9601623. [PMID: 30154868 PMCID: PMC6091255 DOI: 10.1155/2018/9601623] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2018] [Revised: 06/12/2018] [Accepted: 06/20/2018] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells with fibroblast-like morphology and isolated from the bone marrow via plastic adhesion. Their multipotency and immunoregulatory properties make MSCs possible therapeutic agents, and an increasing number of publications and clinical trials have highlighted their potential in regenerative medicine. However, the finite proliferative capacity of MSCs limits their scalability and global dissemination as a standardized therapeutic product. Furthermore, adult tissue provenance could constrain accessibility, impinge on cellular potency, and incur greater exposure to disease-causing pathogens based on the donor. These issues could be circumvented by the derivation of MSCs from pluripotent stem cells. In this paper, we review methods that induce and characterize MSCs derived from induced pluripotent stem cells (iPSCs) and introduce MSC applications to disease modeling, pathogenic mechanisms, and drug discovery. We also discuss the potential applications of MSCs in regenerative medicine including cell-based therapies and issues that should be overcome before iPSC-derived MSC therapy will be applied in the clinic.
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Jalili RB, Kilani RT, Li Y, Khosravi-Maharlooie M, Nabai L, Wang EHC, McElwee KJ, Ghahary A. Fibroblast cell-based therapy prevents induction of alopecia areata in an experimental model. Cell Transplant 2018; 27:994-1004. [PMID: 29871523 PMCID: PMC6050905 DOI: 10.1177/0963689718773311] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Alopecia areata (AA) is an autoimmune hair loss disease with infiltration of
proinflammatory cells into hair follicles. Current therapeutic regimens are unsatisfactory
mainly because of the potential for side effects and/or limited efficacy. Here we report
that cultured, transduced fibroblasts, which express the immunomodulatory molecule
indoleamine 2,3-dioxygenase (IDO), can be applied to prevent hair loss in an experimental
AA model. A single intraperitoneal (IP) injection of IDO-expressing primary dermal
fibroblasts was given to C3H/HeJ mice at the time of AA induction. While 60–70% of mice
that received either control fibroblasts or vehicle injections developed extensive AA,
none of the IDO-expressing fibroblast-treated mice showed new hair loss up to 20 weeks
post injection. IDO cell therapy significantly reduced infiltration of CD4+ and
CD8+ T cells into hair follicles and resulted in decreased expression of
TNF-α, IFN-γ and IL-17 in the skin. Skin draining lymph nodes of IDO fibroblast-treated
mice were significantly smaller, with more CD4+ CD25+
FoxP3+ regulatory T cells and fewer Th17 cells than those of control
fibroblast and vehicle-injected mice. These findings indicate that IP injected
IDO-expressing dermal fibroblasts can control inflammation and thereby prevent AA hair
loss.
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Affiliation(s)
- Reza B Jalili
- 1 Department of Surgery, ICORD (international collaboration on regenerative discoveries), University of British Columbia, Canada
| | - Ruhangiz T Kilani
- 1 Department of Surgery, ICORD (international collaboration on regenerative discoveries), University of British Columbia, Canada
| | - Yunyuan Li
- 1 Department of Surgery, ICORD (international collaboration on regenerative discoveries), University of British Columbia, Canada
| | - Mohsen Khosravi-Maharlooie
- 1 Department of Surgery, ICORD (international collaboration on regenerative discoveries), University of British Columbia, Canada
| | - Layla Nabai
- 1 Department of Surgery, ICORD (international collaboration on regenerative discoveries), University of British Columbia, Canada
| | - Eddy Hsi Chun Wang
- 2 Department of Dermatology and Skin Science, University of British Columbia, Canada
| | - Kevin J McElwee
- 2 Department of Dermatology and Skin Science, University of British Columbia, Canada
| | - Aziz Ghahary
- 1 Department of Surgery, ICORD (international collaboration on regenerative discoveries), University of British Columbia, Canada
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Abstract
Tissues contain multiple different cell types and can be considered to be heterocellular systems. Signaling between different cells allows tissues to achieve phenotypes that no cell type can achieve in isolation. Such emergent tissue-level phenotypes can be said to 'supervene upon' heterocellular signaling. It is proposed here that cancer is also an emergent phenotype that supervenes upon heterocellular signaling. Using colorectal cancer (CRC) as an example, I review how heterotypic cells differentially communicate to support emergent malignancy. Studying tumors as integrated heterocellular systems - rather than as solitary expansions of mutated cells - may reveal novel ways to treat cancer.
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36
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Chabannon C, Kuball J, Bondanza A, Dazzi F, Pedrazzoli P, Toubert A, Ruggeri A, Fleischhauer K, Bonini C. Hematopoietic stem cell transplantation in its 60s: A platform for cellular therapies. Sci Transl Med 2018; 10:10/436/eaap9630. [DOI: 10.1126/scitranslmed.aap9630] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2017] [Accepted: 03/23/2018] [Indexed: 12/11/2022]
Abstract
Over the last 60 years, more than a million patients received hematopoietic cell transplantation. Having incorporated multiple changes in clinical practices, it remains a complex procedure facing a dual challenge: cure of the underlying disease and prevention of relapse while controlling potentially severe complications. Improved understanding of underlying biological processes resulted in the design of innovative therapies engineered from defined cell populations and testing of these therapies as addition or substitution at virtually every step of the procedure. This review provides an overview of these developments, many of them now applied outside the historical field of hematopoietic cell transplantation.
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37
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Inhibition of lymphocyte proliferation: An ability shared by murine mesenchymal stem cells, dermal fibroblasts and chondrocytes. Transpl Immunol 2018; 47:55-61. [DOI: 10.1016/j.trim.2018.02.008] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 02/08/2018] [Accepted: 02/12/2018] [Indexed: 02/06/2023]
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38
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Orekhov PY, Konoplyannikov MA, Baklaushev VP, Kalsin VAA, Averyanov AV, Konopliannikov AG, Habazov RI, Troitskiy AV. Bone marrow stem cells for the critical limb ischemia treatment: biological aspects and clinical application. GENES & CELLS 2018; 13:20-34. [DOI: 10.23868/201805002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/07/2025]
Abstract
Cell therapy is one of the most promising directions in the treatment of critical limb ischemia (CLI). In spite of certain advances achieved in this field in the last decades, which are related to application of bone marrow stem cells (BMSC), a large number of problems still remain unsolved. In this review, we discuss the BMSC biology, mechanisms of their therapeutic effect in the CLI treatment and results of the most notable BMSC-based clinical studies in detail.
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39
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, ElSayed AS, Ashaal AE, Ali MM, El-Shal AS. Mechanistic effects of mesenchymal and hematopoietic stem cells: New therapeutic targets in myocardial infarction. J Cell Biochem 2018; 119:5274-5286. [PMID: 29266431 DOI: 10.1002/jcb.26637] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2017] [Accepted: 12/19/2017] [Indexed: 12/16/2022]
Abstract
Myocardial infarction (MI) results in dysfunction and irreversible loss of cardiomyocytes and is of the most serious health threats today. Mesenchymal stem cells (MSCs) and hematopoietic stem cells (HSCs) have been explored as promising cell therapy in MI and regenerative therapy. Recently, reports investigated the potential therapeutic effects of MSCs or HSCs transplantation after MI in numerous experimental and clinical studies; however, their results are controversy and needs more explorations. The current review is an attempt to clarify the therapeutic potentials of MSCs and HSCs in MI therapy, as well as their possible effects; especially the paracrine one and the exosome-derived stem cell among animal models as well as clinical trials conducted within the last 10 years. In this context, various sources of MSCs and HSCs have been addressed in helping cardiac regeneration by either revitalizing the cardiac stem cells niche or revascularizing the arteries and veins of the heart. In addition, both MSCs and HSCs could produce paracrine mediators and growth factors which led to cardiomyocytes protection, angiogenesis, immunemodulation, antioxidants, anti-apoptotic, anti-inflammatory, antifibrotic, as well as increasing cardiac contractility. Recently, microRNAs (miRNAs), post-transcriptional regulators of gene expression, and long non-coding RNA (lncRNA), a miRNA sponge, are recent stem cell-derived mediators can be promising targets of MSCs and HSCs through their paracrine effects. Although MSCs and HSCs have achieved considerable achievements, however, some challenges still remain that need to be overcome in order to establish it as a successful technique. The present review clarified the mechanistic potentials of MSCs and HSCs especially paracrine effects involved in MI including human and animal studies and the challenges challenges regarding type, differentiation, route, and number of injections.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Mahmoud A Ali
- Biomedical Research Department, Military Armed Forces College of Medicine (AFCM), Cairo, Egypt
| | - Hazem G Ghanem
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Ahmed I Shehata
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Hossam R Handal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | | | - Ahmed E Ashaal
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Mazen M Ali
- Undergraduate Student, Armed Forces College of Medicine, Cairo, Egypt
| | - Amal S El-Shal
- Department of Medical Biochemistry and Molecular biology, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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40
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Poggi A, Varesano S, Zocchi MR. How to Hit Mesenchymal Stromal Cells and Make the Tumor Microenvironment Immunostimulant Rather Than Immunosuppressive. Front Immunol 2018; 9:262. [PMID: 29515580 PMCID: PMC5825917 DOI: 10.3389/fimmu.2018.00262] [Citation(s) in RCA: 85] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2017] [Accepted: 01/30/2018] [Indexed: 12/17/2022] Open
Abstract
Experimental evidence indicates that mesenchymal stromal cells (MSCs) may regulate tumor microenvironment (TME). It is conceivable that the interaction with MSC can influence neoplastic cell functional behavior, remodeling TME and generating a tumor cell niche that supports tissue neovascularization, tumor invasion and metastasization. In addition, MSC can release transforming growth factor-beta that is involved in the epithelial-mesenchymal transition of carcinoma cells; this transition is essential to give rise to aggressive tumor cells and favor cancer progression. Also, MSC can both affect the anti-tumor immune response and limit drug availability surrounding tumor cells, thus creating a sort of barrier. This mechanism, in principle, should limit tumor expansion but, on the contrary, often leads to the impairment of the immune system-mediated recognition of tumor cells. Furthermore, the cross-talk between MSC and anti-tumor lymphocytes of the innate and adaptive arms of the immune system strongly drives TME to become immunosuppressive. Indeed, MSC can trigger the generation of several types of regulatory cells which block immune response and eventually impair the elimination of tumor cells. Based on these considerations, it should be possible to favor the anti-tumor immune response acting on TME. First, we will review the molecular mechanisms involved in MSC-mediated regulation of immune response. Second, we will focus on the experimental data supporting that it is possible to convert TME from immunosuppressive to immunostimulant, specifically targeting MSC.
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Affiliation(s)
- Alessandro Poggi
- Molecular Oncology and Angiogenesis Unit, Policlinico San Martino, Genoa, Italy
| | - Serena Varesano
- Molecular Oncology and Angiogenesis Unit, Policlinico San Martino, Genoa, Italy
| | - Maria Raffaella Zocchi
- Division of Immunology, Transplants and Infectious Diseases, San Raffaele Scientific Institute, Milan, Italy
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41
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Cheung TS, Dazzi F. Mesenchymal-myeloid interaction in the regulation of immunity. Semin Immunol 2018; 35:59-68. [PMID: 29395680 DOI: 10.1016/j.smim.2018.01.002] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2018] [Accepted: 01/24/2018] [Indexed: 12/13/2022]
Abstract
Several studies have demonstrated how different cell types of mesenchymal and myeloid origin can independently exhibit immunoregulatory activities. In response to inflammatory cues, they transcribe a molecular repertoire that restores the tissue microenvironment to what it was before the injury. There is accumulating evidence that stromal and myeloid-derived cells do not act independently but that the establishment of a cross-talk between them is a fundamental requirement. Stromal cells, prompted by inflammatory molecules, orchestrate and initiate myeloid cell recruitment and their functional reprogramming. Once instructed, myeloid cells effect the anti-inflammatory activity or, if alternatively required, enhance immune responses. The cross-talk plays a fundamental role in tissue homeostasis, not only to regulate inflammation, but also to promote tissue regeneration and cancer progression.
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Affiliation(s)
- Tik Shing Cheung
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom
| | - Francesco Dazzi
- School of Cancer and Pharmacological Sciences and KHP Cancer Research UK Centre, King's College London, London, United Kingdom.
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42
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Pinchuk IV, Powell DW. Immunosuppression by Intestinal Stromal Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2018; 1060:115-129. [DOI: 10.1007/978-3-319-78127-3_7] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
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43
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Shafei AES, Ali MA, Ghanem HG, Shehata AI, Abdelgawad AA, Handal HR, Talaat KA, Ashaal AE, El-Shal AS. Mesenchymal stem cell therapy: A promising cell-based therapy for treatment of myocardial infarction. J Gene Med 2017; 19. [PMID: 29044850 DOI: 10.1002/jgm.2995] [Citation(s) in RCA: 111] [Impact Index Per Article: 13.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2017] [Revised: 10/07/2017] [Accepted: 10/07/2017] [Indexed: 12/12/2022] Open
Abstract
For decades, mesenchymal stem (MSCs) cells have been used for cardiovascular diseases as regenerative therapy. This review is an attempt to summarize the types of MSCs involved in myocardial infarction (MI) therapy, as well as its possible mechanisms effects, especially the paracrine one in MI focusing on the studies (human and animal) conducted within the last 10 years. Recently, reports showed that MSC therapy could have infarct-limiting effects after MI in both experimental and clinical trials. In this context, various types of MSCs can help cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Furthermore, MSCs could produce paracrine growth factors that increase the survival of nearby cardiomyocytes, as well as increase angiogenesis through recruitment of stem cell from bone marrow or inducing vessel growth from existing capillaries. Recent research suggests that the paracrine effects of MSCs could be mediated by extracellular vesicles including exosomes. Exosomal microRNAs (miRNAs) released by MSCs are promising therapeutic hotspot target for MI. This could be attributed to the role of miRNA in cardiac biology, including cardiac regeneration, stem cell differentiation, apoptosis, neovascularization, cardiac contractility and cardiac remodeling. Furthermore, gene-modified MSCs could be a recent promising therapy for MI to enhance the paracrine effects of MSCs, including better homing and effective cell targeted tissue regeneration. Although MSC therapy has achieved considerable attention and progress, there are critical challenges that remains to be overcome to achieve the most effective successful cell-based therapy in MI.
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Affiliation(s)
- Ayman El-Sayed Shafei
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | - Mahmoud Ahmed Ali
- Biomedical Research Department, Military Armed Forces College of Medicine, Cairo, Egypt
| | | | | | | | | | | | | | - Amal S El-Shal
- Medical Biochemistry & Molecular Biology Department, Faculty of Medicine, Zagazig University, Zagazig, Egypt
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44
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Ma L, Zhou Z, Zhang D, Yang S, Wang J, Xue F, Yang Y, Yang R. Immunosuppressive function of mesenchymal stem cells from human umbilical cord matrix in immune thrombocytopenia patients. Thromb Haemost 2017; 107:937-50. [DOI: 10.1160/th11-08-0596] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 01/18/2012] [Indexed: 01/12/2023]
Abstract
SummaryHuman umbilical cord matrix/Wharton's Jelly (hUC)-derived mesenchymal stem cells (MSC) have been shown to have marked therapeutic effects in a number of inflammatory diseases and autoimmune diseases in humans based on their potential for immunosuppression and their low immunogenicity. Currently, no data are available on the effectiveness of UC-MSC transplantation in immune thrombocytopenia (ITP) patients. It was the objective of this study to assess the effect of allogeneic UC-MSCs on ITP patients in vitro and in vivo. Peripheral blood mononuclear cells (PBMCs) and bone marrow mononuclear cells (BM-MNCs) from ITP patients and healthy controls were co-cultured with UC-MSCs for three days and seven days, respectively. Flow cytometry and ELISA were applied to assess the various parameters. In PBMCs from ITP patients, the proliferation of autoreactive T, B lymphocytes and destruction of autologous platelets were dramatically suppressed by UC-MSCs. UC-MSCs not only suppressed co-stimulatory molecules CD80, CD40L and FasL expression but also in shifting Th1/Th2/Treg cytokines profile in ITP patients. UC-MSCs obviously reversed the dysfunctions of megakaryocytes by promoting platelet production and decreasing the number of living megakaryocytes as well as early apoptosis. In addition, the level of thrombopoietin was increased significantly. Our clinical study showed that UC-MSCs play a role in alleviating refractory ITP by increasing platelet numbers. These findings suggested that UC-MSCs transplantation might be a potential therapy for ITP.
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45
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Abstract
Stromal cells like synovial fibroblasts gained great interest over the years, since it has become clear that they strongly influence their environment and neighbouring cells. The current review describes the role of synovial fibroblasts as cells of the innate immune system and expands on their involvement in inflammation and cartilage destruction in rheumatoid arthritis (RA). Furthermore, epigenetic changes in RA synovial fibroblasts and studies that focused on the identification of different subsets of synovial fibroblasts are discussed.
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Affiliation(s)
- Caroline Ospelt
- Department of Rheumatology, Center of Experimental Rheumatology, University Hospital and University of Zurich, Zurich, Switzerland
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46
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Devireddy LR, Boxer L, Myers MJ, Skasko M, Screven R. Questions and Challenges in the Development of Mesenchymal Stromal/Stem Cell-Based Therapies in Veterinary Medicine. TISSUE ENGINEERING PART B-REVIEWS 2017; 23:462-470. [DOI: 10.1089/ten.teb.2016.0451] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Affiliation(s)
- Lax R. Devireddy
- Division of Applied Veterinary Research, Center for Veterinary Medicine, US Food and Drug Administration, Laurel, Maryland
| | - Lynne Boxer
- Office of New Animal Drug Evaluation, Center for Veterinary Medicine, US Food and Drug Administration, Rockville, Maryland
| | - Michael J. Myers
- Division of Applied Veterinary Research, Center for Veterinary Medicine, US Food and Drug Administration, Laurel, Maryland
| | - Mark Skasko
- Office of New Animal Drug Evaluation, Center for Veterinary Medicine, US Food and Drug Administration, Rockville, Maryland
| | - Rudell Screven
- Division of Applied Veterinary Research, Center for Veterinary Medicine, US Food and Drug Administration, Laurel, Maryland
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47
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Microgrooved-surface topography enhances cellular division and proliferation of mouse bone marrow-derived mesenchymal stem cells. PLoS One 2017; 12:e0182128. [PMID: 28846679 PMCID: PMC5573154 DOI: 10.1371/journal.pone.0182128] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 07/12/2017] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stem cells’ (MSCs) fate is largely determined by the various topographical features and a range of extracellular matrix (ECM) components present in their niches. Apart from maintaining structural stability, they regulate cell morphology, division, proliferation, migration and differentiation among others. Traditional MSC cultures, which are mainly based on two-dimensional smooth surfaces of culture dishes and plates, do not provide topographical cues similar to in vivo three-dimensional niches, impacting various cellular processes. Therefore, we culture the mouse bone marrow-derived MSCs on microgrooved bearing surface, partially mimicking in vivo reticulated niche, to study its effect on morphology, pluripotency factor-associated stemness, cell division and rate of proliferation. Following culture, morphological features, and MSC-specific marker gene expression, such as CD29, CD44, Sca-1 along with HSC (Haematopoietic stem cell)-specific markers like CD34, CD45, CD11b were evaluated by microscopy and immunophenotyping, respectively. HSC is another type of bone marrow stem cell population, which concertedly interacts with MSC during various functions, including haematopoiesis. In addition, mesenchymal stem cells were further analyzed for gene expression of pluripotency-associated transcription factors such as Oct3/4, Sox-2, Nanog and Myc, as well as differentiated into adipocytes, osteocytes and chondrocytes. Our results show that microgrooved surface-cultured mesenchymal stem cells (MMSCs) expressed higher levels of expected cell surface and pluripotency-associated markers and proliferated more rapidly (2–3×fold) with higher percentage of cells in S/G2-M-phase, consequently giving rise to higher cell yield compared to standard culture flask-grown cells (MSCs), taken as control. Furthermore, both MSCs and MMSCs showed considerable accumulation of intracellular lipid-droplets, higher alkaline phosphatase activity and secretion of extracellular matrix that are characteristics of adipogenesis, osteogenesis and chondrogenesis, respectively.
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48
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Li M, Zhao Y, Hao H, Han W, Fu X. Theoretical and practical aspects of using fetal fibroblasts for skin regeneration. Ageing Res Rev 2017; 36:32-41. [PMID: 28238941 DOI: 10.1016/j.arr.2017.02.005] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2016] [Revised: 02/21/2017] [Accepted: 02/21/2017] [Indexed: 12/17/2022]
Abstract
Cutaneous wounding in late-gestational fetal or postnatal humans results in scar formation without any skin appendages. Early or mid- gestational skin healing in humans is characterized by the absence of scaring in a process resembling regeneration. Tremendous cellular and molecular mechanisms contribute to this distinction, and fibroblasts play critical roles in scar or scarless wound healing. This review discussed the different repair mechanisms involved in wound healing of fibroblasts at different developmental stages and further confirmed that fetal fibroblast transplantation resulted in reduced scar healing in vivo. We also discussed the possible problem in fetal fibroblast transplantation for wound repair. We proposed the use of small molecules to improve the regenerative potential of repairing cells in the wound given that remodeling of the wound microenvironment into a regenerative microenvironment in adults might improve skin regeneration.
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49
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[Mesenchymal stem/stroma cells : Therapeutic potential in the treatment of autoimmune diseases]. Z Rheumatol 2017; 75:786-794. [PMID: 27481118 DOI: 10.1007/s00393-016-0161-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stem and stromal cells (MSC) are propagated for the treatment of autoimmune and autoinflammatory processes. These cells can be relatively easily obtained from various tissues. The MSC feature anti-inflammatory and immunosuppressive properties in vitro as well as in animal models. Initial reports on the clinical application of MSC for various diseases are available, some with promising results and so far no reported toxicity; however, data from phase III studies are still lacking and crucial questions are still unanswered. The MSC preparations used are heterogeneous and also differ depending on the source and it is unclear whether autologous (own) or allogeneic (foreign) MSC are more suitable for therapeutic use. Long-term consequences, such as possible malignant transformation and possible endogenous tumor growth stimulation cannot be completely excluded. Ultimately, these questions can only be answered through randomized controlled trials for defined clinical indications with defined MSC.
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50
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Tykocinski LO, Lauffer AM, Bohnen A, Kaul NC, Krienke S, Tretter T, Adam I, Mohapatra SR, Saikali P, Löhning M, Neidhart M, Gay S, Oezen I, Platten M, Opitz CA, Lorenz HM. Synovial Fibroblasts Selectively Suppress Th1 Cell Responses through IDO1-Mediated Tryptophan Catabolism. THE JOURNAL OF IMMUNOLOGY 2017; 198:3109-3117. [DOI: 10.4049/jimmunol.1600600] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Accepted: 02/13/2017] [Indexed: 11/19/2022]
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