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Wei S, Li M, Wang Q, Zhao Y, Du F, Chen Y, Deng S, Shen J, Wu K, Yang J, Sun Y, Gu L, Li X, Li W, Chen M, Ling X, Yu L, Xiao Z, Dong L, Wu X. Mesenchymal Stromal Cells: New Generation Treatment of Inflammatory Bowel Disease. J Inflamm Res 2024; 17:3307-3334. [PMID: 38800593 PMCID: PMC11128225 DOI: 10.2147/jir.s458103] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Accepted: 05/09/2024] [Indexed: 05/29/2024] Open
Abstract
Inflammatory bowel disease (IBD) is a chronic inflammatory disease of the gastrointestinal tract, which has a high recurrence rate and is incurable due to a lack of effective treatment. Mesenchymal stromal cells (MSCs) are a class of pluripotent stem cells that have recently received a lot of attention due to their strong self-renewal ability and immunomodulatory effects, and a large number of experimental and clinical models have confirmed the positive therapeutic effect of MSCs on IBD. In preclinical studies, MSC treatment for IBD relies on MSCs paracrine effects, cell-to-cell contact, and its mediated mitochondrial transfer for immune regulation. It also plays a therapeutic role in restoring the intestinal mucosal barrier through the homing effect, regulation of the intestinal microbiome, and repair of intestinal epithelial cells. In the latest clinical trials, the safety and efficacy of MSCs in the treatment of IBD have been confirmed by transfusion of autologous or allogeneic bone marrow, umbilical cord, and adipose MSCs, as well as their derived extracellular vesicles. However, regarding the stable and effective clinical use of MSCs, several concerns emerge, including the cell sources, clinical management (dose, route and frequency of administration, and pretreatment of MSCs) and adverse reactions. This article comprehensively summarizes the effects and mechanisms of MSCs in the treatment of IBD and its advantages over conventional drugs, as well as the latest clinical trial progress of MSCs in the treatment of IBD. The current challenges and future directions are also discussed. This review would add knowledge into the understanding of IBD treatment by applying MSCs.
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Affiliation(s)
- Shulin Wei
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Mingxing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Qin Wang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yueshui Zhao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Fukuan Du
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yu Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Shuai Deng
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jing Shen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Ke Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Jiayue Yang
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Yuhong Sun
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Li Gu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiaobing Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Wanping Li
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Meijuan Chen
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xiao Ling
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lei Yu
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Zhangang Xiao
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
| | - Lishu Dong
- Department of Obstetrics, Luzhou Maternal & Child Health Hospital (Luzhou Second People’s Hospital), Luzhou, Sichuan, 646100, People’s Republic of China
| | - Xu Wu
- Cell Therapy & Cell Drugs of Luzhou Key Laboratory, Department of Pharmacology, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, 646100, People’s Republic of China
- South Sichuan Institute of Translational Medicine, Luzhou, Sichuan, 646100, People’s Republic of China
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Xu W, Yang Y, Li N, Hua J. Interaction between Mesenchymal Stem Cells and Immune Cells during Bone Injury Repair. Int J Mol Sci 2023; 24:14484. [PMID: 37833933 PMCID: PMC10572976 DOI: 10.3390/ijms241914484] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 10/15/2023] Open
Abstract
Fractures are the most common large organ trauma in humans. The initial inflammatory response promotes bone healing during the initial post-fracture phase, but chronic and persistent inflammation due to infection or other factors does not contribute to the healing process. The precise mechanisms by which immune cells and their cytokines are regulated in bone healing remain unclear. The use of mesenchymal stem cells (MSCs) for cellular therapy of bone injuries is a novel clinical treatment approach. Bone progenitor MSCs not only differentiate into bone, but also interact with the immune system to promote the healing process. We review in vitro and in vivo studies on the role of the immune system and bone marrow MSCs in bone healing and their interactions. A deeper understanding of this paradigm may provide clues to potential therapeutic targets in the healing process, thereby improving the reliability and safety of clinical applications of MSCs to promote bone healing.
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Affiliation(s)
| | | | - Na Li
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
| | - Jinlian Hua
- Shaanxi Centre of Stem Cells Engineering & Technology, College of Veterinary Medicine, Northwest A&F University, Yangling, Xianyang 712100, China; (W.X.); (Y.Y.)
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Zhou Y, Cheng L, Liu L, Li X. NK cells are never alone: crosstalk and communication in tumour microenvironments. Mol Cancer 2023; 22:34. [PMID: 36797782 PMCID: PMC9933398 DOI: 10.1186/s12943-023-01737-7] [Citation(s) in RCA: 59] [Impact Index Per Article: 29.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2022] [Accepted: 01/30/2023] [Indexed: 02/18/2023] Open
Abstract
Immune escape is a hallmark of cancer. The dynamic and heterogeneous tumour microenvironment (TME) causes insufficient infiltration and poor efficacy of natural killer (NK) cell-based immunotherapy, which becomes a key factor triggering tumour progression. Understanding the crosstalk between NK cells and the TME provides new insights for optimising NK cell-based immunotherapy. Here, we present new advances in direct or indirect crosstalk between NK cells and 9 specialised TMEs, including immune, metabolic, innervated niche, mechanical, and microbial microenvironments, summarise TME-mediated mechanisms of NK cell function inhibition, and highlight potential targeted therapies for NK-TME crosstalk. Importantly, we discuss novel strategies to overcome the inhibitory TME and provide an attractive outlook for the future.
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Affiliation(s)
- Yongqiang Zhou
- grid.32566.340000 0000 8571 0482The First School of Clinical Medicine, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000 China ,grid.412643.60000 0004 1757 2902Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China ,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Lu Cheng
- Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China
| | - Lu Liu
- grid.412643.60000 0004 1757 2902Department of Pediatrics, The First Hospital of Lanzhou University, Lanzhou, China
| | - Xun Li
- The First School of Clinical Medicine, Lanzhou University, 222 Tianshui South Road, Lanzhou, 730000, China. .,Department of General Surgery, The First Hospital of Lanzhou University, Lanzhou, China. .,Key Laboratory of Biotherapy and Regenerative Medicine of Gansu Province, Lanzhou, China.
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Sheikholeslami A, Fazaeli H, Kalhor N, Khoshandam M, Eshagh Hoseini SJ, Sheykhhasan M. Use of Mesenchymal Stem Cells in Crohn's Disease and Perianal Fistulas: A Narrative Review. Curr Stem Cell Res Ther 2023; 18:76-92. [PMID: 34530720 DOI: 10.2174/1574888x16666210916145717] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/08/2021] [Accepted: 06/15/2021] [Indexed: 11/22/2022]
Abstract
Crohn's Disease (CD), which usually leads to anal fistulas among patients, is the most important inflammatory bowel disease that causes morbidity in many people around the world. This review article proposes using MSCs as a hopeful therapeutic strategy for CD and anal fistula treatment in both preclinical and clinical conditions. Finally, darvadstrocel, a cell-based medication to treat complex anal fistulas in adults, as the only European Medicines Agency (EMA)-approved product for the treatment of anal fistulas in CD is addressed. Although several common therapies, such as surgery and anti-tumor necrosis factor-alpha (TNF-α) drugs as well as a combination of these methods is used to improve this disease, however, due to the low effectiveness of these treatments, the use of new strategies with higher efficiency is still recommended. Cell therapy is among the new emerging therapeutic strategies that have attracted great attention from clinicians due to its unique capabilities. One of the most widely used cell sources administrated in cell therapy is mesenchymal stem cell (MSC). This review article will discuss preclinical and clinical studies about MSCs as a potent and promising therapeutic option in the treatment of CD and anal fistula.
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Affiliation(s)
- Azar Sheikholeslami
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Hoda Fazaeli
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom,Iran
| | - Naser Kalhor
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | - Mohadeseh Khoshandam
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
| | | | - Mohsen Sheykhhasan
- Department of Mesenchymal Stem Cells, Academic Center for Education, Culture and Research (ACECR), Qom Branch, Qom, Iran
- Department of Research Center for Molecular Medicine, Hamadan University of Medical Sciences, Hamadan, Iran
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Pezzanite LM, Chow L, Strumpf A, Johnson V, Dow SW. Immune Activated Cellular Therapy for Drug Resistant Infections: Rationale, Mechanisms, and Implications for Veterinary Medicine. Vet Sci 2022; 9:610. [PMID: 36356087 PMCID: PMC9695672 DOI: 10.3390/vetsci9110610] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 10/18/2022] [Accepted: 10/31/2022] [Indexed: 11/06/2022] Open
Abstract
Antimicrobial resistance and biofilm formation both present challenges to treatment of bacterial infections with conventional antibiotic therapy and serve as the impetus for development of improved therapeutic approaches. Mesenchymal stromal cell (MSC) therapy exerts an antimicrobial effect as demonstrated in multiple acute bacterial infection models. This effect can be enhanced by pre-conditioning the MSC with Toll or Nod-like receptor stimulation, termed activated cellular therapy (ACT). The purpose of this review is to summarize the current literature on mechanisms of antimicrobial activity of MSC with emphasis on enhanced effects through receptor agonism, and data supporting use of ACT in treatment of bacterial infections in veterinary species including dogs, cats, and horses with implications for further treatment applications. This review will advance the field's understanding of the use of activated antimicrobial cellular therapy to treat infection, including mechanisms of action and potential therapeutic applications.
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Affiliation(s)
- Lynn M. Pezzanite
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Lyndah Chow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
| | - Alyssa Strumpf
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, The Ohio State University, Columbus, OH 43210, USA
| | - Valerie Johnson
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Michigan State University, Lansing, MI 48824, USA
| | - Steven W. Dow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
- Department of Microbiology, Immunology, and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO 80523, USA
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6
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Current Progress in Vascular Engineering and Its Clinical Applications. Cells 2022; 11:cells11030493. [PMID: 35159302 PMCID: PMC8834640 DOI: 10.3390/cells11030493] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2022] [Revised: 01/28/2022] [Accepted: 01/29/2022] [Indexed: 02/04/2023] Open
Abstract
Coronary heart disease (CHD) is caused by narrowing or blockage of coronary arteries due to atherosclerosis. Coronary artery bypass grafting (CABG) is widely used for the treatment of severe CHD cases. Although autologous vessels are a preferred choice, healthy autologous vessels are not always available; hence there is a demand for tissue engineered vascular grafts (TEVGs) to be used as alternatives. However, producing clinical grade implantable TEVGs that could healthily survive in the host with long-term patency is still a great challenge. There are additional difficulties in producing small diameter (<6 mm) vascular conduits. As a result, there have not been TEVGs that are commercially available. Properties of vascular scaffolds such as tensile strength, thrombogenicity and immunogenicity are key factors that determine the biocompatibility of TEVGs. The source of vascular cells employed to produce TEVGs is a limiting factor for large-scale productions. Advanced technologies including the combined use of natural and biodegradable synthetic materials for scaffolds in conjunction with the use of mesenchyme stem cells or induced pluripotent stem cells (iPSCs) provide promising solutions for vascular tissue engineering. The aim of this review is to provide an update on various aspects in this field and the current status of TEVG clinical applications.
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Sallustio F, Picerno A, Tatullo M, Rampino A, Rengo C, Valletta A, Torretta S, Falcone RM. Toll-Like Receptors in Stem/Progenitor Cells. Handb Exp Pharmacol 2022; 276:175-212. [PMID: 34595583 DOI: 10.1007/164_2021_539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
One of the bridges that control the cross-talk between the innate and adaptive immune systems is toll-like receptors (TLRs). TLRs interact with molecules shared and maintained by the source pathogens, but also with endogenous molecules derived from injured tissues (damage/danger-associated molecular patterns - DAMPs). This is likely why some kinds of stem/progenitor cells (SCs) have been found to express TLRs. The role of TLRs in regulating basal motility, proliferation, processes of differentiation, self-renewal, and immunomodulation has been demonstrated in these cells. In this book chapter, we will discuss the many different functions assumed by the TLRs in SCs, pointing out that, depending on the context and the type of ligands they perceive, they may have different effects. In addition, the role of TLR in SC's response to specific tissue damage and in reparative processes will be addressed, as well as how the discovery of molecules mediating TLR signaling's differential function may be decisive for the development of new therapeutic strategies. Given the available studies on TLRs in SCs, the significance of TLRs in sensing an injury to stem/progenitor cells and evaluating their action and reparative activity, which depends on the circumstances, will be discussed here. It could also be possible that SCs used in therapy could theoretically be exposed to TLR ligands, which could modulate their in vivo therapeutic potential. In this context, we need to better understand the mechanisms of action of TLRs on SCs and learn how to regulate these receptors and their downstream pathways in a precise way in order to modulate SC proliferation, survival, migration, and differentiation in the pathological environment. In this way, cell therapy may be strengthened and made safer in the future.
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Affiliation(s)
- Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy.
| | - Angela Picerno
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", Bari, Italy
| | - Marco Tatullo
- Department of Basic Medical Sciences, Neurosciences and Sense Organs-University of Bari "Aldo Moro", Bari, Italy
| | - Antonio Rampino
- Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Carlo Rengo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Alessandra Valletta
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Silvia Torretta
- Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Rosa Maria Falcone
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
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Ehnert S, Relja B, Schmidt-Bleek K, Fischer V, Ignatius A, Linnemann C, Rinderknecht H, Huber-Lang M, Kalbitz M, Histing T, Nussler AK. Effects of immune cells on mesenchymal stem cells during fracture healing. World J Stem Cells 2021; 13:1667-1695. [PMID: 34909117 PMCID: PMC8641016 DOI: 10.4252/wjsc.v13.i11.1667] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Revised: 03/31/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
In vertebrates, bone is considered an osteoimmune system which encompasses functions of a locomotive organ, a mineral reservoir, a hormonal organ, a stem cell pool and a cradle for immune cells. This osteoimmune system is based on cooperatively acting bone and immune cells, cohabitating within the bone marrow. They are highly interdependent, a fact that is confounded by shared progenitors, mediators, and signaling pathways. Successful fracture healing requires the participation of all the precursors, immune and bone cells found in the osteoimmune system. Recent evidence demonstrated that changes of the immune cell composition and function may negatively influence bone healing. In this review, first the interplay between different immune cell types and osteoprogenitor cells will be elaborated more closely. The separate paragraphs focus on the specific cell types, starting with the cells of the innate immune response followed by cells of the adaptive immune response, and the complement system as mediator between them. Finally, a brief overview on the challenges of preclinical testing of immune-based therapeutic strategies to support fracture healing will be given.
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Affiliation(s)
- Sabrina Ehnert
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Borna Relja
- Experimental Radiology, Department of Radiology and Nuclear Medicine, Otto-von-Guericke University, Magdeburg 39120, Germany
| | - Katharina Schmidt-Bleek
- Julius Wolff Institute and Berlin Institute of Health Center of Regenerative Therapies, Charité - University Medicine Berlin, Berlin 13353, Germany
| | - Verena Fischer
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Anita Ignatius
- Institute of Orthopedic Research and Biomechanics, Ulm University Medical Center, Ulm 89091, Germany
| | - Caren Linnemann
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Helen Rinderknecht
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Markus Huber-Lang
- Institute for Clinical and Experimental Trauma-Immunology (ITI), University Hospital Ulm, Ulm 89091, Germany
| | - Miriam Kalbitz
- Department of Trauma and Orthopedic Surgery, University Hospital Erlangen Friedrich-Alexander University Erlangen-Nürnberg (FAU), Erlangen 91054, Germany
| | - Tina Histing
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
| | - Andreas K Nussler
- Siegfried Weller Research Institute at the BG Trauma Center Tübingen, Department of Trauma and Reconstructive Surgery, University of Tübingen, Tübingen 72076, Germany
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Aldrich ED, Cui X, Murphy CA, Lim KS, Hooper GJ, McIlwraith CW, Woodfield TBF. Allogeneic mesenchymal stromal cells for cartilage regeneration: A review of in vitro evaluation, clinical experience, and translational opportunities. Stem Cells Transl Med 2021; 10:1500-1515. [PMID: 34387402 PMCID: PMC8550704 DOI: 10.1002/sctm.20-0552] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 05/19/2021] [Accepted: 06/06/2021] [Indexed: 12/14/2022] Open
Abstract
The paracrine signaling, immunogenic properties and possible applications of mesenchymal stromal cells (MSCs) for cartilage tissue engineering and regenerative medicine therapies have been investigated through numerous in vitro, animal model and clinical studies. The emerging knowledge largely supports the concept of MSCs as signaling and modulatory cells, exerting their influence through trophic and immune mediation rather than as a cell replacement therapy. The virtues of allogeneic cells as a ready‐to‐use product with well‐defined characteristics of cell surface marker expression, proliferative ability, and differentiation capacity are well established. With clinical applications in mind, a greater focus on allogeneic cell sources is evident, and this review summarizes the latest published and upcoming clinical trials focused on cartilage regeneration adopting allogeneic and autologous cell sources. Moreover, we review the current understanding of immune modulatory mechanisms and the role of trophic factors in articular chondrocyte‐MSC interactions that offer feasible targets for evaluating MSC activity in vivo within the intra‐articular environment. Furthermore, bringing labeling and tracking techniques to the clinical setting, while inherently challenging, will be extremely informative as clinicians and researchers seek to bolster the case for the safety and efficacy of allogeneic MSCs. We therefore review multiple promising approaches for cell tracking and labeling, including both chimerism studies and imaging‐based techniques, that have been widely explored in vitro and in animal models. Understanding the distribution and persistence of transplanted MSCs is necessary to fully realize their potential in cartilage regeneration techniques and tissue engineering applications.
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Affiliation(s)
- Ellison D Aldrich
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, Department of Orthopedic Surgery & Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand.,School of Veterinary Science, Massey University, Palmerston North, New Zealand
| | - Xiaolin Cui
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, Department of Orthopedic Surgery & Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - Caroline A Murphy
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, Department of Orthopedic Surgery & Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - Khoon S Lim
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, Department of Orthopedic Surgery & Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - Gary J Hooper
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, Department of Orthopedic Surgery & Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
| | - C Wayne McIlwraith
- Orthopedic Research Center, C. Wayne McIlwraith Translational Medicine Institute, Colorado State University, Fort Collins, Colorado, USA
| | - Tim B F Woodfield
- Christchurch Regenerative Medicine and Tissue Engineering (CReaTE) Group, Department of Orthopedic Surgery & Musculoskeletal Medicine, University of Otago, Christchurch, New Zealand
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10
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Mesenchymal stromal cells in the bone marrow niche consist of multi-populations with distinct transcriptional and epigenetic properties. Sci Rep 2021; 11:15811. [PMID: 34349154 PMCID: PMC8338933 DOI: 10.1038/s41598-021-94186-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2020] [Accepted: 06/30/2021] [Indexed: 12/29/2022] Open
Abstract
Although multiple studies have investigated the mesenchymal stem and progenitor cells (MSCs) that give rise to mature bone marrow, high heterogeneity in their morphologies and properties causes difficulties in molecular separation of their distinct populations. In this study, by taking advantage of the resolution of the single cell transcriptome, we analyzed Sca-1 and PDGFR-α fraction in the mouse bone marrow tissue. The single cell transcriptome enabled us to further classify the population into seven populations according to their gene expression profiles. We then separately obtained the seven populations based on candidate marker genes, and specified their gene expression properties and epigenetic landscape by ATAC-seq. Our findings will enable to elucidate the stem cell niche signal in the bone marrow microenvironment, reconstitute bone marrow in vitro, and shed light on the potentially important role of identified subpopulation in various clinical applications to the treatment of bone- and bone marrow-related diseases.
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11
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Sharma A, Chakraborty A, Jaganathan BG. Review of the potential of mesenchymal stem cells for the treatment of infectious diseases. World J Stem Cells 2021; 13:568-593. [PMID: 34249228 PMCID: PMC8246252 DOI: 10.4252/wjsc.v13.i6.568] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/08/2021] [Revised: 04/07/2021] [Accepted: 06/03/2021] [Indexed: 02/06/2023] Open
Abstract
The therapeutic value of mesenchymal stem cells (MSCs) for the treatment of infectious diseases and the repair of disease-induced tissue damage has been explored extensively. MSCs inhibit inflammation, reduce pathogen load and tissue damage encountered during infectious diseases through the secretion of antimicrobial factors for pathogen clearance and they phagocytose certain bacteria themselves. MSCs dampen tissue damage during infection by downregulating the levels of pro-inflammatory cytokines, and inhibiting the excessive recruitment of neutrophils and proliferation of T cells at the site of injury. MSCs aid in the regeneration of damaged tissue by differentiating into the damaged cell types or by releasing paracrine factors that direct tissue regeneration, differentiation, and wound healing. In this review, we discuss in detail the various mechanisms by which MSCs help combat pathogens, tissue damage associated with infectious diseases, and challenges in utilizing MSCs for therapy.
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Affiliation(s)
- Amit Sharma
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Anuja Chakraborty
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
| | - Bithiah Grace Jaganathan
- Stem Cell and Cancer Biology Group, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati 781039, India
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12
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Kim GB, Shon OJ, Seo MS, Choi Y, Park WT, Lee GW. Mesenchymal Stem Cell-Derived Exosomes and Their Therapeutic Potential for Osteoarthritis. BIOLOGY 2021; 10:285. [PMID: 33915850 PMCID: PMC8066608 DOI: 10.3390/biology10040285] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2021] [Revised: 03/28/2021] [Accepted: 03/29/2021] [Indexed: 12/18/2022]
Abstract
Exosomes are nano-sized vesicles (50-150 nm in diameter) that contain nucleic acids (e.g., microRNA and messenger RNA), functional proteins, and bioactive lipids. They are secreted by various types of cells, including B cells, T cells, reticulocytes, dendritic cells, mast cells, epithelial cells, and mesenchymal stem cells (MSCs). They perform a wide variety of functions, including the repair of damaged tissues, regulation of immune responses, and reduction in inflammation. When considering the limitations of MSCs, including issues in standardization and immunogenicity, MSC-derived exosomes have advantages such as small dimensions, low immunogenicity, and lack of requirement for additional procedures for culture expansion or delivery. MSC-derived exosomes have shown outstanding therapeutic effects through chondro-protective and anti-inflammatory properties. MSC-derived exosomes may enable a new therapeutic paradigm for the treatment of osteoarthritis. However, further research is needed to prove their clinical effectiveness and feasibility.
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Affiliation(s)
- Gi Beom Kim
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
| | - Oog-Jin Shon
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
| | - Min-Soo Seo
- Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea;
| | - Young Choi
- Department of Orthopedic Surgery, Kosin University College of Medicine, Kosin University Gospel Hospital, 262 Gamcheon-ro, Seogu, Busan 49267, Korea;
| | - Wook Tae Park
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
| | - Gun Woo Lee
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University, Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea; (G.B.K.); (O.-J.S.); (W.T.P.)
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13
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Najafi-Ghalehlou N, Roudkenar MH, Langerodi HZ, Roushandeh AM. Taming of Covid-19: potential and emerging application of mesenchymal stem cells. Cytotechnology 2021; 73:253-298. [PMID: 33776206 PMCID: PMC7982879 DOI: 10.1007/s10616-021-00461-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Accepted: 02/17/2021] [Indexed: 12/24/2022] Open
Abstract
Coronavirus Disease 2019 (COVID-19) caused by the Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has turned out to cause a pandemic, with a sky scraping mortality. The virus is thought to cause tissue injury by affecting the renin-angiotensin system. Also, the role of the over-activated immune system is noteworthy, leading to severe tissue injury via the cytokine storms. Thus it would be feasible to modulate the immune system response in order to attenuate the disease severity, as well as treating the patients. Today different medicines are being administered to the patients, but regardless of the efficacy of these treatments, adverse effects are pretty probable. Meanwhile, mesenchymal stem cells (MSCs) prove to be an effective candidate for treating the patients suffering from COVID-19 pneumonia, owing to their immunomodulatory and tissue-regenerative potentials. So far, several experiments have been conducted; transplanting MSCs and results are satisfying with no adverse effects being reported. This paper aims to review the recent findings regarding the novel coronavirus and the conducted experiments to treat patients suffering from COVID-19 pneumonia utilizing MSCs.
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Affiliation(s)
- Nima Najafi-Ghalehlou
- Department of Medical Laboratory Sciences, Faculty of Paramedicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehryar Habibi Roudkenar
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Medical Biotechnology Department, Paramedicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
| | - Habib Zayeni Langerodi
- Guilan Rheumatology Research Center (GRRC), Guilan University of Medical Sciences, Rasht, Iran
| | - Amaneh Mohammadi Roushandeh
- Burn and Regenerative Medicine Research Center, Velayat Hospital, School of Medicine, Guilan University of Medical Sciences, Rasht, Iran
- Anatomical Sciences Department, Medicine Faculty, Guilan University of Medical Sciences, Rasht, Iran
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14
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Moloudizargari M, Govahi A, Fallah M, Rezvanfar MA, Asghari MH, Abdollahi M. The mechanisms of cellular crosstalk between mesenchymal stem cells and natural killer cells: Therapeutic implications. J Cell Physiol 2020; 236:2413-2429. [PMID: 32892356 DOI: 10.1002/jcp.30038] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2020] [Revised: 08/11/2020] [Accepted: 08/21/2020] [Indexed: 12/18/2022]
Abstract
Mesenchymal stem cells (MSCs) are mesenchymal precursors of various origins, with well-known immunomodulatory effects. Natural killer (NK) cells, the major cells of the innate immune system, are critical for the antitumor and antiviral defenses; however, in certain cases, they may be the main culprits in the pathogenesis of some NK-related conditions such as autoimmunities and hematological malignancies. On the other hand, these cells seem to be the major responders in beneficial phenomena like graft versus leukemia. Substantial data suggest that MSCs can variably affect NK cells and can be affected by these cells. Accordingly, acquiring a profound understanding of the crosstalk between MSCs and NK cells and the involved mechanisms seems to be a necessity to develop therapeutic approaches based on such interactions. Therefore, in this study, we made a thorough review of the existing literature on the interactions between MSCs and NK cells with a focus on the underlying mechanisms. The current knowledge herein suggests that MSCs possess a great potential to be used as tools for therapeutic targeting of NK cells in disease context and that preconditioning of MSCs, as well as their genetic manipulation before administration, may provide a wider variety of options in terms of eliciting more specific and desirable therapeutic outcomes. Nevertheless, our knowledge regarding the effects of MSCs on NK cells is still in its infancy, and further studies with well-defined conditions are warranted herein.
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Affiliation(s)
- Milad Moloudizargari
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Ali Govahi
- Department of Immunology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Marjan Fallah
- Department of Pharmacology and Toxicology, Medicinal Plant Research Centre, Faculty of Pharmacy, Islamic Azad University, Amol, Iran
| | - Mohammad A Rezvanfar
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
| | - Mohammad H Asghari
- Department of Pharmacology and Toxicology, School of Medicine, Babol University of Medical Sciences, Babol, Iran
| | - Mohammad Abdollahi
- Toxicology and Diseases Group, Pharmaceutical Sciences Research Center, The Institute of Pharmaceutical Sciences (TIPS), and Department of Toxicology and Pharmacology, School of Pharmacy, Tehran University of Medical Sciences (TUMS), Tehran, Iran
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15
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Wu X, Jiang J, Gu Z, Zhang J, Chen Y, Liu X. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res Ther 2020; 11:345. [PMID: 32771052 PMCID: PMC7414268 DOI: 10.1186/s13287-020-01855-9] [Citation(s) in RCA: 187] [Impact Index Per Article: 37.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a subset of heterogeneous non-hematopoietic fibroblast-like cells that can differentiate into cells of multiple lineages, such as chondrocytes, osteoblasts, adipocytes, myoblasts, and others. These multipotent MSCs can be found in nearly all tissues but mostly located in perivascular niches, playing a significant role in tissue repair and regeneration. Additionally, MSCs interact with immune cells both in innate and adaptive immune systems, modulating immune responses and enabling immunosuppression and tolerance induction. Understanding the biology of MSCs and their roles in clinical treatment is crucial for developing MSC-based cellular therapy for a variety of pathological conditions. Here, we review the progress in the study on the mechanisms underlying the immunomodulatory and regenerative effects of MSCs; update the medical translation of MSCs, focusing on the registration trials leading to regulatory approvals; and discuss how to improve therapeutic efficacy and safety of MSC applications for future.
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Affiliation(s)
- Xiaomo Wu
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
- Department of Biomedicine, University of Basel, Klingelbergstr 70, CH-4056, Basel, Switzerland
| | - Ju Jiang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Zhongkai Gu
- The Institute of Biomedical Sciences, Fudan University, Mingdao Building, Dongan Road 131, Shanghai, 200032, China
| | - Jinyan Zhang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Yang Chen
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
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16
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Liu S, Liu F, Zhou Y, Jin B, Sun Q, Guo S. Immunosuppressive Property of MSCs Mediated by Cell Surface Receptors. Front Immunol 2020; 11:1076. [PMID: 32849489 PMCID: PMC7399134 DOI: 10.3389/fimmu.2020.01076] [Citation(s) in RCA: 65] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2020] [Accepted: 05/04/2020] [Indexed: 12/16/2022] Open
Abstract
In the past decade, mesenchymal stem cells (MSCs) tend to exhibit inherent tropism for refractory inflammatory diseases and engineered MSCs have appeared on the market as therapeutic agents. Recently, engineered MSCs target to cell surface molecules on immune cells has been a new strategy to improve MSC applications. In this review, we discuss the roles of multiple receptors (ICAM-1, Gal-9, PD-L1, TIGIT, CD200, and CXCR4) in the process of MSCs' immunosuppressive properties. Furthermore, we discuss the principles and strategies for developing receptor-regulated MSCs and their mechanisms of action and the challenges of using MSCs as immunosuppressive therapies.
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Affiliation(s)
- Siyu Liu
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Fei Liu
- Department of Breast Surgery, Shengjing Hospital of China Medical University, Shenyang, China
| | - You Zhou
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Baeku Jin
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Qiang Sun
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
| | - Shu Guo
- Department of Plastic Surgery, The First Hospital of China Medical University, Shenyang, China
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17
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Eom YW, Kang SH, Kim MY, Lee JI, Baik SK. Mesenchymal stem cells to treat liver diseases. ANNALS OF TRANSLATIONAL MEDICINE 2020; 8:563. [PMID: 32775364 PMCID: PMC7347787 DOI: 10.21037/atm.2020.02.163] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Mesenchymal stem cells (MSCs) are being developed for stem cell therapy and can be efficiently used in regenerative medicine. To date, more than 1,000 clinical trials have used MSCs; of these, more than 80 clinical trials have targeted liver disease. MSCs migrate to damaged liver tissues, differentiate into hepatocytes, reduce liver inflammatory responses, reduce liver fibrosis, and act as antioxidants. According to the reported literature, MSCs are safe, have no side effects, and improve liver function; however, their regenerative therapeutic effects are unsatisfactory. Here, we explain, in detail, the basic therapeutic effects and recent clinical advances of MSCs. Furthermore, we discuss future research directions for improving the regenerative therapeutic effects of MSCs.
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Affiliation(s)
- Young Woo Eom
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Seong Hee Kang
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Moon Young Kim
- Cell Therapy and Tissue Engineering Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Jong In Lee
- Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - Soon Koo Baik
- Regeneration Medicine Research Center, Yonsei University Wonju College of Medicine, Wonju, Korea.,Department of Internal Medicine, Yonsei University Wonju College of Medicine, Wonju, Korea
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18
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The Achievements and Challenges of Mesenchymal Stem Cell-Based Therapy in Inflammatory Bowel Disease and Its Associated Colorectal Cancer. Stem Cells Int 2020; 2020:7819824. [PMID: 32256612 PMCID: PMC7104387 DOI: 10.1155/2020/7819824] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2019] [Revised: 01/07/2020] [Accepted: 02/03/2020] [Indexed: 02/08/2023] Open
Abstract
Approximately 18.1 × 106 new cases of cancer were recorded globally in 2018, out of which 9.6 million died. It is known that people who have Inflammatory Bowel Disease (IBD) turn to be prone to increased risks of developing colorectal cancer (CRC), which has global incident and mortality rates of 10.2% and 9.2%, respectively. Over the years, conventional treatments of IBD and its associated CRC have been noted to provide scarce desired results and often with severe complications. The introduction of biological agents as a better therapeutic approach has witnessed a great deal of success in both experimental and clinical models. With regard to mesenchymal stem cell (MSC) therapy, the ability of these cells to actively proliferate, undergo plastic differentiation, trigger strong immune regulation, exhibit low immunogenicity, and express abundant trophic factors has ensured their success in regenerative medicine and immune intervention therapies. Notwithstanding, MSC-based therapy is still confronted with some challenges including the likelihood of promoting tumor growth and metastasis, and possible overestimated therapeutic potentials. We review the success story of MSC-based therapy in IBD and its associated CRC as documented in experimental models and clinical trials, examining some of the challenges encountered and possible ways forward to producing an optimum MSC therapeutic imparts.
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19
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Behnke J, Kremer S, Shahzad T, Chao CM, Böttcher-Friebertshäuser E, Morty RE, Bellusci S, Ehrhardt H. MSC Based Therapies-New Perspectives for the Injured Lung. J Clin Med 2020; 9:jcm9030682. [PMID: 32138309 PMCID: PMC7141210 DOI: 10.3390/jcm9030682] [Citation(s) in RCA: 117] [Impact Index Per Article: 23.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2020] [Revised: 02/25/2020] [Accepted: 02/28/2020] [Indexed: 12/11/2022] Open
Abstract
Chronic lung diseases pose a tremendous global burden. At least one in four people suffer from severe pulmonary sequelae over the course of a lifetime. Despite substantial improvements in therapeutic interventions, persistent alleviation of clinical symptoms cannot be offered to most patients affected to date. Despite broad discrepancies in origins and pathomechanisms, the important disease entities all have in common the pulmonary inflammatory response which is central to lung injury and structural abnormalities. Mesenchymal stem cells (MSC) attract particular attention due to their broadly acting anti-inflammatory and regenerative properties. Plenty of preclinical studies provided congruent and convincing evidence that MSC have the therapeutic potential to alleviate lung injuries across ages. These include the disease entities bronchopulmonary dysplasia, asthma and the different forms of acute lung injury and chronic pulmonary diseases in adulthood. While clinical trials are so far restricted to pioneering trials on safety and feasibility, preclinical results point out possibilities to boost the therapeutic efficacy of MSC application and to take advantage of the MSC secretome. The presented review summarizes the most recent advances and highlights joint mechanisms of MSC action across disease entities which provide the basis to timely tackle this global disease burden.
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Affiliation(s)
- Judith Behnke
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
| | - Sarah Kremer
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
| | - Tayyab Shahzad
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
| | - Cho-Ming Chao
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
- Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Cardiopulmonary Institute (CPI), German Center for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany;
| | | | - Rory E. Morty
- Department of Lung Development and Remodeling, Max Planck Institute for Heart and Lung Research, German Center for Lung Research (DZL), Ludwigstrasse 43, 61231 Bad Nauheim, Germany;
| | - Saverio Bellusci
- Department of Internal Medicine II, Universities of Giessen and Marburg Lung Center (UGMLC), Cardiopulmonary Institute (CPI), German Center for Lung Research (DZL), Aulweg 130, 35392 Giessen, Germany;
| | - Harald Ehrhardt
- Department of General Pediatrics and Neonatology, Justus-Liebig-University, Universities of Giessen and Marburg Lung Center (UGMLC), German Center for Lung Research (DZL), Feulgenstrasse 12, 35392 Gießen, Germany; (J.B.); (S.K.); (T.S.); (C.-M.C.)
- Correspondence: ; Tel.: +49-985-43400; Fax: +49-985-43419
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20
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Therapeutic Mesenchymal Stromal Cells for Immunotherapy and for Gene and Drug Delivery. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2020; 16:204-224. [PMID: 32071924 PMCID: PMC7012781 DOI: 10.1016/j.omtm.2020.01.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess several fairly unique properties that, when combined, make them ideally suited for cellular-based immunotherapy and as vehicles for gene and drug delivery for a wide range of diseases and disorders. Key among these are: (1) their relative ease of isolation from a variety of tissues; (2) the ability to be expanded in culture without a loss of functionality, a property that varies to some degree with tissue source; (3) they are relatively immune-inert, perhaps obviating the need for precise donor/recipient matching; (4) they possess potent immunomodulatory functions that can be tailored by so-called licensing in vitro and in vivo; (5) the efficiency with which they can be modified with viral-based vectors; and (6) their almost uncanny ability to selectively home to damaged tissues, tumors, and metastases following systemic administration. In this review, we summarize the latest research in the immunological properties of MSCs, their use as immunomodulatory/anti-inflammatory agents, methods for licensing MSCs to customize their immunological profile, and their use as vehicles for transferring both therapeutic genes in genetic disease and drugs and genes designed to destroy tumor cells.
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21
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Jiang W, Xu J. Immune modulation by mesenchymal stem cells. Cell Prolif 2020; 53:e12712. [PMID: 31730279 PMCID: PMC6985662 DOI: 10.1111/cpr.12712] [Citation(s) in RCA: 380] [Impact Index Per Article: 76.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 09/11/2019] [Accepted: 10/08/2019] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) can be derived from various adult tissues with multipotent and self-renewal abilities. The characteristics of presenting no major ethical concerns, having low immunogenicity and possessing immune modulation functions make MSCs promising candidates for stem cell therapies. MSCs could promote inflammation when the immune system is underactivated and restrain inflammation when the immune system is overactivated to avoid self-overattack. These cells express many immune suppressors to switch them from a pro-inflammatory phenotype to an anti-inflammatory phenotype, resulting in immune effector cell suppression and immune suppressor cell activation. We would discuss the mechanisms governing the immune modulation function of these cells in this review, especially the immune-suppressive effects of MSCs.
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Affiliation(s)
- Wei Jiang
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesHealth Science CenterShenzhen UniversityShenzhenChina
- Department of Anatomy, Histology & Developmental BiologyHealth Science CenterShenzhen UniversityShenzhenChina
| | - Jianyong Xu
- Guangdong Provincial Key Laboratory of Regional Immunity and DiseasesHealth Science CenterShenzhen UniversityShenzhenChina
- Department of Anatomy, Histology & Developmental BiologyHealth Science CenterShenzhen UniversityShenzhenChina
- Department of ImmunologyHealth Science CenterShenzhen UniversityShenzhenChina
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22
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Galland S, Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J Pathol 2019; 250:555-572. [PMID: 31608444 PMCID: PMC7217065 DOI: 10.1002/path.5357] [Citation(s) in RCA: 107] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/03/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose – based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack, a handful of cell surface markers – MSCs likely encompass several subpopulations, which may have diverse properties. Their diversity may explain, at least in part, the pleiotropic functions that they display in different physiological and pathological settings. In the context of tissue injury, MSCs can respectively promote and attenuate inflammation during the early and late phases of tissue repair. They may thereby act as sensors of the inflammatory response and secrete mediators that boost or temper the response as required by the stage of the reparatory and regenerative process. MSCs are also implicated in regulating tumor development, in which they are increasingly recognized to play a complex role. Thus, MSCs can both promote and constrain tumor progression by directly affecting tumor cells via secreted mediators and cell–cell interactions and by modulating the innate and adaptive immune response. This review summarizes our current understanding of MSC involvement in tumor development and highlights the mechanistic underpinnings of their implication in tumor growth and progression. © 2020 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Sabine Galland
- Laboratory of Experimental Pathology, Institute of Pathology, CHUV, Lausanne, Switzerland
| | - Ivan Stamenkovic
- Laboratory of Experimental Pathology, Institute of Pathology, CHUV, Lausanne, Switzerland
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23
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Hu CHD, Kosaka Y, Marcus P, Rashedi I, Keating A. Differential Immunomodulatory Effects of Human Bone Marrow-Derived Mesenchymal Stromal Cells on Natural Killer Cells. Stem Cells Dev 2019; 28:933-943. [DOI: 10.1089/scd.2019.0059] [Citation(s) in RCA: 26] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Affiliation(s)
- Chia-Hsuan Donna Hu
- Cell Therapy Translational Research Laboratory, Princess Margaret Cancer Center, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Yoko Kosaka
- Cell Therapy Translational Research Laboratory, Princess Margaret Cancer Center, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Paula Marcus
- Cell Therapy Translational Research Laboratory, Princess Margaret Cancer Center, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Iran Rashedi
- Cell Therapy Translational Research Laboratory, Princess Margaret Cancer Center, Krembil Research Institute, University Health Network, Toronto, ON, Canada
| | - Armand Keating
- Cell Therapy Translational Research Laboratory, Princess Margaret Cancer Center, Krembil Research Institute, University Health Network, Toronto, ON, Canada
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24
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Najar M, Fayyad-Kazan M, Merimi M, Burny A, Bron D, Fayyad-Kazan H, Meuleman N, Lagneaux L. Mesenchymal Stromal Cells and Natural Killer Cells: A Complex Story of Love and Hate. Curr Stem Cell Res Ther 2019; 14:14-21. [PMID: 30207245 DOI: 10.2174/1574888x13666180912125736] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2018] [Revised: 09/03/2018] [Accepted: 09/07/2018] [Indexed: 12/29/2022]
Abstract
Mesenchymal stromal cells (MSCs), characterized by both multidifferentiation potential and potent immunomodulatory capacity, represent a promising, safe and powerful cell based-therapy for repairing tissue damage and/or treating diseases associated with aberrant immune responses. Natural killer (NK) cells are granular lymphocytes of the innate immune system that function alone or in combination with other immune cells to combat both tumors and virally infected cells. After their infusion, MSCs are guided by host inflammatory elements and can interact with different immune cells, particularly those of the innate immune system. Although some breakthroughs have been achieved in understanding these interactions, much remains to be determined. In this review, we discuss the complex interactions between NK cells and MSCs, particularly the importance of improving the therapeutic value of MSCs.
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Affiliation(s)
- Mehdi Najar
- Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), and Department of Medicine, University of Montreal, Montreal, QC, Canada.,Laboratory of Physiology, Ethnopharmacology and Genetics, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Mohammad Fayyad-Kazan
- Laboratory of Experimental Hematology, Institut Jules Bordet, Universite Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium
| | - Makram Merimi
- Laboratory of Experimental Hematology, Institut Jules Bordet, Universite Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium
| | - Arsène Burny
- Laboratory of Experimental Hematology, Institut Jules Bordet, Universite Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium
| | - Dominique Bron
- Laboratory of Experimental Hematology, Institut Jules Bordet, Universite Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
| | - Nathalie Meuleman
- Hematology Department, Institut Jules Bordet, Universite Libre de Bruxelles, 121 Boulevard de Waterloo, 1000 Bruxelles, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Universite Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
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25
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Sallustio F, Curci C, Stasi A, De Palma G, Divella C, Gramignoli R, Castellano G, Gallone A, Gesualdo L. Role of Toll-Like Receptors in Actuating Stem/Progenitor Cell Repair Mechanisms: Different Functions in Different Cells. Stem Cells Int 2019; 2019:6795845. [PMID: 31089331 PMCID: PMC6476106 DOI: 10.1155/2019/6795845] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/19/2018] [Indexed: 02/07/2023] Open
Abstract
Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer.
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Affiliation(s)
- Fabio Sallustio
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari 70124, Italy
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Claudia Curci
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Alessandra Stasi
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Giuseppe De Palma
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
- Institutional Biobank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Chiara Divella
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - Giuseppe Castellano
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Anna Gallone
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Loreto Gesualdo
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
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26
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Manufacturing of primed mesenchymal stromal cells for therapy. Nat Biomed Eng 2019; 3:90-104. [PMID: 30944433 DOI: 10.1038/s41551-018-0325-8] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 11/14/2018] [Indexed: 12/11/2022]
Abstract
Mesenchymal stromal cells (MSCs) for basic research and clinical applications are manufactured and developed as unique cell products by many different manufacturers and laboratories, often under different conditions. The lack of standardization of MSC identity has limited consensus around which MSC properties are relevant for specific outcomes. In this Review, we examine how the choice of media, cell source, culture environment and storage affects the phenotype and clinical utility of MSC-based products, and discuss the techniques better suited to prime MSCs with specific phenotypes of interest and the need for the continued development of standardized assays that provide quality assurance for clinical-grade MSCs. Bioequivalence between cell products and batches must be investigated rather than assumed, so that the diversity of phenotypes between differing MSC products can be accounted for to identify products with the highest therapeutic potential and to preserve their safety in clinical treatments.
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27
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Najar M, Fayyad-Kazan M, Merimi M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L. Reciprocal immuno-biological alterations occur during the co-culture of natural killer cells and adipose tissue-derived mesenchymal stromal cells. Cytotechnology 2019; 71:375-388. [PMID: 30632032 DOI: 10.1007/s10616-019-00294-6] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2018] [Accepted: 01/07/2019] [Indexed: 02/07/2023] Open
Abstract
Due to their immune-therapeutic value, adipose tissue-derived mesenchymal stromal cells (AT-MSCs) require a better characterization of their interplay with natural killer (NK) cells known to contribute to the graft-versus-leukemia effects. When cultivated together, AT-MSCs showed cellular cytotoxicity and were therefore killed by NK cells in an activating-cytokine dependent manner. In the presence of AT-MSCs, both ligands and receptors known to drive NK cell interactions were significantly altered. During this co-culture, the proliferation of NK cells was slightly reduced, while their IFN-γ and TNF-α secretion was significantly increased. NK cells displayed sustained degranulation accompanied by increased discharge of their cytolytic granules (perforin, granzymes A and B). On the other hand, activated NK cells reduced the expression of serpins C1 and B9 in AT-MSCs. Collectively, reciprocal immuno-biological alterations occur during the co-culture of NK cells and AT-MSCs. Understanding these changes will increase the safety and efficacy of cell-based immuno-oncotherapy.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Osteoarthritis Research Unit, University of Montreal Hospital Research Center (CRCHUM), 900 Saint-Denis, R11.424, Montreal, QC, H2X 0A9, Canada
| | - Mohammad Fayyad-Kazan
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium.
| | - Makram Merimi
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium.,Laboratory of Physiology, Genetics and Ethnopharmacology, Faculty of Sciences, University Mohammed Premier, Oujda, Morocco
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121 Boulevard de Waterloo, 1000, Brussels, Belgium
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
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28
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Antebi B, Walker KP, Mohammadipoor A, Rodriguez LA, Montgomery RK, Batchinsky AI, Cancio LC. The effect of acute respiratory distress syndrome on bone marrow-derived mesenchymal stem cells. Stem Cell Res Ther 2018; 9:251. [PMID: 30257702 PMCID: PMC6158906 DOI: 10.1186/s13287-018-0981-3] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 08/07/2018] [Accepted: 08/13/2018] [Indexed: 01/14/2023] Open
Abstract
Background It is known that, following a physiological insult, bone marrow-derived mesenchymal stem cells (MSCs) mobilize and home to the site of injury. However, the effect of injury on the function of endogenous MSCs is unknown. In this study, MSCs harvested from the bone marrow of swine with or without acute respiratory distress syndrome (ARDS) were assessed for their characteristics and therapeutic function. Methods MSCs were harvested from three groups of anesthetized and mechanically ventilated swine (n = 3 in each group): 1) no ARDS (‘Uninjured’ group); 2) ARDS induced via smoke inhalation and 40% burn and treated with inhaled epinephrine (‘Injured Treated’ group); and 3) ARDS without treatment (‘Injured Untreated’ group). Cellular evaluation of the three groups included: flow cytometry for MSC markers; colony forming unit-fibroblast (CFU-F) assay; proliferative and metabolic capacity; gene expression using quantitative real-time polymerase chain reaction (qRT-PCR); and a lipopolysaccharide (LPS) challenge, with or without coculture with mononuclear cells (MNCs), for evaluation of their protein secretion profile using Multiplex. Statistical analysis was performed using one- or two-way analysis of variance (ANOVA) with a Tukey’s post-test; a p-value less than 0.05 was considered statistically significant. Results Cells from all groups exhibited nearly 100% expression of MSC surface markers and retained their multidifferentiation capacity. However, the MSCs from the ‘Injured Untreated’ group generated a significantly higher number of colonies compared with the other two groups (p < 0.0001), indicative of increased clonogenic capacity following ARDS. Following an LPS challenge, the MSCs from the ‘Injured Untreated’ group exhibited a significant reduction in their proliferative capacity (p = 0.0002), significant downregulation in the expression of high-mobility group box 1 (HMGB1; p < 0.001), Toll-like receptor (TLR)-4 (p < 0.01), and vascular endothelial growth factor (VEGF; p < 0.05) genes, and significantly diminished secretory capacity for the inflammatory mediators interleukin (IL)-6 (p < 0.0001), IL-8 (p < 0.05), and tumor necrosis factor (TNF)-α (p < 0.05) compared with the ‘Uninjured’ group. Conclusions The results suggest that, following ARDS, there is an increase in the clonogenic capacity of MSCs to increase the available stem cell pool in vivo. However, MSCs harvested from subjects with ARDS seem to exhibit a diminished capacity to proliferate, express regenerative signals, and secrete pro/anti-inflammatory mediators.
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Affiliation(s)
- Ben Antebi
- United States Army Institute of Surgical Research, San Antonio, TX, USA.
| | - Kerfoot P Walker
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Arezoo Mohammadipoor
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,Oak Ridge Institute for Science and Education, Oak Ridge, TN, USA
| | - Luis A Rodriguez
- United States Army Institute of Surgical Research, San Antonio, TX, USA
| | | | - Andriy I Batchinsky
- United States Army Institute of Surgical Research, San Antonio, TX, USA.,The Geneva Foundation, Tacoma, WA, USA
| | - Leopoldo C Cancio
- United States Army Institute of Surgical Research, San Antonio, TX, USA
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29
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Magne B, Lataillade JJ, Trouillas M. Mesenchymal Stromal Cell Preconditioning: The Next Step Toward a Customized Treatment For Severe Burn. Stem Cells Dev 2018; 27:1385-1405. [PMID: 30039742 DOI: 10.1089/scd.2018.0094] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the last century, the clinical management of severe skin burns significantly progressed with the development of burn care units, topical antimicrobials, resuscitation methods, early eschar excision surgeries, and skin grafts. Despite these considerable advances, the present treatment of severe burns remains burdensome, and patients are highly susceptible to skin engraftment failure, infections, organ dysfunction, and hypertrophic scarring. Recent researches have focused on mesenchymal stromal cell (MSC) therapy and hold great promises for tissue repair, as reported in several animal studies and clinical cases. In the present review, we will provide an up-to-date outlook of the pathophysiology of severe skin burns, clinical treatment modalities and current limitations. We will then focus on MSCs and their potential in the burn wound healing both in in vitro and in vivo studies. A specific attention will be paid to the cell preconditioning approach, as a means of improving the MSC efficacy in the treatment of major skin burns. In particular, we will debate how several preconditioning cues would modulate the MSC properties to better match up with the burn pathophysiology in the course of the cell therapy. Finally, we will discuss the clinical interest and feasibility of a MSC-based therapy in comparison to their paracrine derivatives, including microvesicles and conditioned media for the treatment of major skin burn injuries.
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Affiliation(s)
- Brice Magne
- INSERM U1197-Institut de Recherche Biomédicale des Armées (IRBA)/Antenne Centre de Transfusion Sanguine des Armées (CTSA) , Clamart, France
| | - Jean-Jacques Lataillade
- INSERM U1197-Institut de Recherche Biomédicale des Armées (IRBA)/Antenne Centre de Transfusion Sanguine des Armées (CTSA) , Clamart, France
| | - Marina Trouillas
- INSERM U1197-Institut de Recherche Biomédicale des Armées (IRBA)/Antenne Centre de Transfusion Sanguine des Armées (CTSA) , Clamart, France
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30
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Alimoradi E, Sisakhtnezhad S, Akrami H. Thymoquinone influences the expression of genes involved in self-renewal and immunomodulatory potential of mouse bone marrow-derived mesenchymal stem cells in vitro. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2018; 60:216-224. [PMID: 29763882 DOI: 10.1016/j.etap.2018.05.001] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2018] [Revised: 05/04/2018] [Accepted: 05/06/2018] [Indexed: 06/08/2023]
Abstract
Thymoquinone (TQ) is an active ingredient of some medicinal herbs. Despite extensive studies on the biological and pharmacological properties of TQ, its effect on the characteristics of stem cells remains to be clarified. Therefore, this study was aimed to investigate the effect of TQ on viability, proliferation and immunomodulatory potential of mouse bone marrow-derived mesenchymal stem cells (BM-MSCs) in vitro. The BM-MSCs were isolated from young NMRI mice. The cytotoxic effect of TQ on the BM-MSCs was evaluated using MTT assay. Then, the effect of TQ on the proliferation of BM-MSCs and the mRNA expression of genes involved in self-renewal and immunomodulatory potential of MSCs was assessed by the cell counting and real-time PCR assays. Results showed that TQ reduces the number of BM-MSCs in a dose- and time-dependent manner. In addition, the half-maximal inhibitory concentration values of TQ on the BM-MSCs were 8 μg/ml at 24h and 4 μg/ml at 48 and 72h after treatment. Furthermore, about 90% of the BM-MSCs were alive after treatment with concentrations ≤2 μg/ml of TQ for 24h. The results of cell counting assay indicated that TQ at concentrations of 1-2 μg/ml significantly enhanced the proliferation of BM-MSCs (P < 0.05). The gene expression analysis also showed that Tlr3, Tlr4, Ccl2, Ccl3, Sox2, and Rex1 are overexpressed (Fold change ≥1.5) in the TQ-treated BM-MSCs compared with the untreated samples. In conclusion, these findings propose that TQ may regulate self-renewal and immunomodulatory potential of MSCs. However, the exact mechanisms and the roles of this regulation are required to be elucidated in further study.
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Affiliation(s)
- Elham Alimoradi
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
| | | | - Hassan Akrami
- Department of Biology, Faculty of Science, Razi University, Kermanshah, Iran
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31
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Gupta N, Sinha R, Krasnodembskaya A, Xu X, Nizet V, Matthay MA, Griffin JH. The TLR4-PAR1 Axis Regulates Bone Marrow Mesenchymal Stromal Cell Survival and Therapeutic Capacity in Experimental Bacterial Pneumonia. Stem Cells 2018; 36:796-806. [PMID: 29396891 PMCID: PMC5918231 DOI: 10.1002/stem.2796] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Revised: 12/19/2017] [Accepted: 12/31/2017] [Indexed: 01/01/2023]
Abstract
Bone marrow derived mesenchymal stromal cells have been shown to have significant therapeutic effects in experimental models of pneumonia and lung injury. The current study examined the roles of the toll like receptor 4 (TLR4) and protease activated receptor 1 (PAR1) pathways on mesenchymal stromal cell (MSC) survival and therapeutic activity in a murine model of pneumonia. MSCs from TLR4 -/- and R41Q-PAR1 mutated mice were isolated to test the effect of mutating these specific pathways on MSC survival when exposed to cytotoxic stimuli in vitro. An Escherichia coli pneumonia model was used to assess the effect of these specific pathways on MSC therapeutic activity in vivo. Our results showed that mutation of either the TLR4 or PAR1 pathways in MSCs impaired cell survival under conditions of inflammatory stress in vitro, and eliminated their therapeutic efficacy in vivo. Also, stimulation of the TLR4 pathway on MSCs led to secretion of low levels of prothrombin by MSCs, while disrupting the TLR4 pathway impaired canonical signaling through PAR1 in response to thrombin. Therefore, this study demonstrates that both TLR4 and PAR1 are required for MSC survival under inflammatory conditions in vitro and therapeutic capacity in vivo, and that the TLR4 pathway regulates signaling through PAR1 on MSCs. Stem Cells 2018;36:796-806.
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Affiliation(s)
- N Gupta
- University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093,The Scripps Research Institute, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037,Corresponding Author: Naveen Gupta, MD, Assistant Professor of Medicine, Pulmonary and Critical Care, University of California, San Diego, Assistant Adjunct Professor of Molecular Medicine, The Scripps Research Institute, ; , Phone: (415) 717-6136
| | - R Sinha
- The Scripps Research Institute, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037
| | - A Krasnodembskaya
- Queen’s University, School of Medicine, Dentistry and Biomedical Sciences, Centre for Experimental Medicine, Belfast, UK
| | - X Xu
- The Scripps Research Institute, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037
| | - V Nizet
- University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093
| | - MA Matthay
- University of California, San Francisco School of Medicine, 505 Parnassus Ave, San Francisco, CA 94143
| | - JH Griffin
- University of California, San Diego School of Medicine, 9500 Gilman Drive, La Jolla, CA 92093,The Scripps Research Institute, Department of Molecular Medicine, 10550 North Torrey Pines Road, La Jolla, CA 92037
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32
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Kaundal U, Bagai U, Rakha A. Immunomodulatory plasticity of mesenchymal stem cells: a potential key to successful solid organ transplantation. J Transl Med 2018; 16:31. [PMID: 29448956 PMCID: PMC5815241 DOI: 10.1186/s12967-018-1403-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2017] [Accepted: 02/07/2018] [Indexed: 02/06/2023] Open
Abstract
Organ transplantation remains to be a treatment of choice for patients suffering from irreversible organ failure. Immunosuppressive (IS) drugs employed to maintain the allograft have shown excellent short-term graft survival, but, their long-term use could contribute to immunological and non-immunological risk factors, resulting in graft dysfunctionalities. Upcoming IS regimes have highlighted the use of cell-based therapies, which can eliminate the risk of drug-borne toxicities while maintaining efficacy of the treatment. Mesenchymal stem cells (MSCs) have been considered as an invaluable cell type, owing to their unique immunomodulatory properties, which makes them desirable for application in transplant settings, where hyper-activation of the immune system is evident. The immunoregulatory potential of MSCs holds true for preclinical studies while achieving it in clinical studies continues to be a challenge. Understanding the biological factors responsible for subdued responses of MSCs in vivo would allow uninhibited use of this therapy for countless conditions. In this review, we summarize the variations in the preclinical and clinical studies utilizing MSCs, discuss the factors which might be responsible for variability in outcome and propose the advancements likely to occur in future for using this as a "boutique/personalised therapy" for patient care.
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Affiliation(s)
- Urvashi Kaundal
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
- Department of Zoology, Panjab University, Sector 14, Chandigarh, India
| | - Upma Bagai
- Department of Zoology, Panjab University, Sector 14, Chandigarh, India
| | - Aruna Rakha
- Department of Translational and Regenerative Medicine, Postgraduate Institute of Medical Education and Research, Sector 12, Chandigarh, India
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33
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Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L. Immunological impact of Wharton's Jelly mesenchymal stromal cells and natural killer cell co-culture. Mol Cell Biochem 2018; 447:111-124. [PMID: 29380244 DOI: 10.1007/s11010-018-3297-9] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2017] [Accepted: 01/23/2018] [Indexed: 12/20/2022]
Abstract
Due to their easier isolation, multilineage potential, and immunomodulatory capacity, Wharton's Jelly-derived mesenchymal stromal cells (WJ-MSCs) exhibit promising efficacy in the field of regenerative medicine and immunotherapy. Characterization of WJ-MSCs-natural killer (NK) cells crosstalk is required for ameliorating the medicinal value of WJ-MSCs. Here, we revealed that the outcome of WJ-MSCs-NK cells crosstalk varied according to the type of cytokines (IL-2, IL-12, IL-15 and IL-21) utilized to activate NK cells. Differently activated NK cells exerted distinct cytotoxicities against WJ-MSCs causing their probable death. Cell surface ligands (CD112, CD155, ULPB-3) and receptors (LAIR, CD226, CD314, CD335, CD336 and CD337) governing the interaction between NK cells and their targets, exhibited altered expression profiles following the co-culture with WJ-MSCs. Although partly inhibited NK cell proliferation, WJ-MSCs enhanced activated NK-cell-mediated secretion of IFN-γ and TNF-α. Moreover, WJ-MSCs reinforced NK cells' degranulation as well as secretion of perforin and granzymes. On the other hand, WJ-MSCs displayed only slight increase in ROS generation but significant decrease in A1 and C1 serpins expression following co-culture with activated NK cells. Altogether, our results highlight that WJ-MSCs-NK cells interaction may affect both cell type features and, therefore, their therapeutic properties.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
| | - Mohammad Fayyad-Kazan
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium.
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
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34
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Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L. Immunomodulatory effects of foreskin mesenchymal stromal cells on natural killer cells. J Cell Physiol 2018; 233:5243-5254. [PMID: 29194614 DOI: 10.1002/jcp.26305] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Accepted: 11/28/2017] [Indexed: 12/25/2022]
Abstract
Foreskin-mesenchymal stromal cells (FSK-MSCs) are immune-privileged thus making them valuable immunotherapeutic cell product. Characterization of the relationship between FSK-MSCs and natural killer (NK) cells is essential to improve cell-based therapy. In the present study, we studied for the first time FSK-MSCs-NK interaction and showed that the result of such cross talk was robustly dependent on the type of cytokines (IL-2, IL-12, IL-15, and IL-21) employed to activate NK cells. Distinctly activated-NK cells showed uneven cytotoxicity against FSK-MSCs, triggering their death in fine. The expression of different cell-surface ligands (CD112, CD155, ULPB-3) and receptors (LAIR, KIRs) ensuring such interaction was altered following co-culture of both populations. Despite their partial negative effect on NK cell proliferation, FSK-MSCs boosted the capacity of activated NK-cells to secrete IFN-γ and TNF-α. Moreover, FSK-MSCs enhanced degranulation of NK cells, reinforced secretion of perforin and granzymes, while only modestly increased ROS production. On the other hand, FSK-MSCs-mediated expression of C1 and B9 serpins was significantly lowered in the presence of activated NK cells. Altogether, our results highlight major immunological changes following FSK-MSCs-NK interaction. Understanding these outcomes will therefore enhance the value of the therapeutic strategy.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
| | - Mohammad Fayyad-Kazan
- Institut de Biologie et de Médecine Moléculaires, Université Libre de Bruxelles, Gosselies, Belgium
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo, Bruxelles, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, Boulevard de Waterloo, Bruxelles, Belgium
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
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Najar M, Fayyad-Kazan M, Meuleman N, Bron D, Fayyad-Kazan H, Lagneaux L. Mesenchymal stromal cells of the bone marrow and natural killer cells: cell interactions and cross modulation. J Cell Commun Signal 2018; 12:673-688. [PMID: 29350342 DOI: 10.1007/s12079-018-0448-4] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2017] [Accepted: 01/09/2018] [Indexed: 12/16/2022] Open
Abstract
Bone marrow-derived mesenchymal stromal cells (BM-MSCs) are multipotent progenitor cells that have shown promise for several different therapeutic applications. As they are able to modulate the function of several types of immune cells, BM-MSCs are highly important in the field of cell-based immunotherapy. Understanding BM-MSC-natural killer (NK) cell interactions is crucial for improving their therapeutic efficiency. Here, we observed that the type of NK cell-activating cytokine (e.g., IL-2, IL-12, IL-15 and IL-21) strongly influenced the outcomes of their interactions with BM-MSCs. The expression patterns of the ligands (CD112, CD155, ULPB-3) and receptors (LAIR, NCR) mediating the cross-talk between BM-MSCs and NK cells were critically modulated following co-culture. BM-MSCs partially impaired NK cell proliferation but up-regulated their secretion of IFN-γ and TNF-α. As they are cytotoxic, activated NK cells induced the killing of BM-MSCs. Indeed, BM-MSCs triggered the degranulation of NK cells and increased their release of perforin and granzymes. Interestingly, activated NK cells induced ROS generation within BM-MSCs that caused their decreased viability and reduced expression of serpin B9. Collectively, our observations reveal that BM-MSC-NK cell interactions may impact the immunobiology of both cell types. The therapeutic potential of BM-MSCs will be significantly improved once these issues are well characterized.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
| | - Mohammad Fayyad-Kazan
- Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium.
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium.,Hematology Department, Institut Jules Bordet, Université Libre de Bruxelles, 121, Boulevard de Waterloo, 1000, Bruxelles, Belgium
| | - Hussein Fayyad-Kazan
- Laboratory of Cancer Biology and Molecular Immunology, Faculty of Sciences I, Lebanese University, Hadath, Lebanon
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Brussels, Belgium
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Najar M, Krayem M, Meuleman N, Bron D, Lagneaux L. Mesenchymal Stromal Cells and Toll-Like Receptor Priming: A Critical Review. Immune Netw 2017; 17:89-102. [PMID: 28458620 PMCID: PMC5407987 DOI: 10.4110/in.2017.17.2.89] [Citation(s) in RCA: 78] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2017] [Revised: 02/24/2017] [Accepted: 02/25/2017] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal Stromal Cells (MSCs) are potential cellular candidates for several immunotherapy purposes. Their multilineage potential and immunomodulatory properties make them interesting tools for the treatment of various immunological diseases. However, depending on the local microenvironment, diverse biological functions of MSCs can be modulated. Indeed, during infections such as obtained following TLR-agonist engagement (called as TLR priming), the phenotype, multilineage potential, hematopoietic support and immunomodulatory capacity of MSCs can present critical changes, which could further affect their therapeutic potential. Thus, for appropriate clinical application of MSCs, it is important to well know and understand these effects in particular during infectious episodes and to find the suitable experimental settings to study that. Pre-stimulation of MSCs with a specific TLR ligand may serve as an effective priming step to modulate one of its function to achieve a desired therapeutic issue.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
| | - Mohammad Krayem
- Laboratory of Oncology and Experimental Surgery, Institut Jules Bordet, Université Libre de Bruxelles, Brussels 1000, Belgium
| | - Nathalie Meuleman
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles (ULB), Campus Erasme, Belgium
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Shirjang S, Mansoori B, Solali S, Hagh MF, Shamsasenjan K. Toll-like receptors as a key regulator of mesenchymal stem cell function: An up-to-date review. Cell Immunol 2016; 315:1-10. [PMID: 28284487 DOI: 10.1016/j.cellimm.2016.12.005] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2016] [Revised: 12/07/2016] [Accepted: 12/24/2016] [Indexed: 02/07/2023]
Abstract
Understanding the role of toll-like receptors (TLRs) in the immunomodulation potential, differentiation, migration, and survival of mesenchymal stem cells (MSCs) is absolutely vital to fully exploiting their MSC-based therapeutic potential. Furthermore, through recognition of exogenous or endogenous ligands produced upon injury, TLRs have been linked to allograft rejection and maintenance of chronic inflammatory diseases, including Crohn's disease, rheumatoid arthritis. Characterizing the effect of TLRs in biological control of MSCs fate and function could improve our knowledge about the MSC-based cell therapy and immunotherapy. In this paper, we outline the impacts of TLR activation and mechanisms on MSCs immunomodulatory functions, differentiation, migration, and survivability. Moreover, we indicate that the expression patterns of TLRs in MSCs from different sources.
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Affiliation(s)
- Solmaz Shirjang
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Behzad Mansoori
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Saeed Solali
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Karim Shamsasenjan
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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Castro-Manrreza ME. Participation of mesenchymal stem cells in the regulation of immune response and cancer development. BOLETIN MEDICO DEL HOSPITAL INFANTIL DE MEXICO 2016; 73:380-387. [PMID: 29421282 DOI: 10.1016/j.bmhimx.2016.10.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2016] [Accepted: 10/24/2016] [Indexed: 12/15/2022] Open
Abstract
The relevance of the microenvironment in the initiation, promotion, and progression of cancer has been postulated. Mesenchymal stem cells (MSCs) have been identified as important components of the tumor stroma, which are capable of affecting the development of cancer through various mechanisms. In particular, MSCs immunosuppressive properties play an important role. It has been shown that bone marrow-derived and other healthy tissues-derived MSCs are capable of regulating the immune response by affecting the activation, maturation, proliferation, differentiation, and effector function of cells of the immune system, such as neutrophils, macrophages, dendritic cells, natural killer cells (NK) and T-lymphocytes. Similar mechanisms have been identified in MSCs associated with different types of tumors, where they generate an immunosuppressive microenvironment by decreasing the cytotoxic activity of T-lymphocytes and NK cells, skew macrophage differentiation towards an M2 phenotype, and decrease the secretion of Th1-type cytokines. Also, the cytokines, chemokines, and factors secreted by the transformed cells or other cells from the tumor stroma are capable of modulating the functions of MSCs.
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Malcolm DW, Sorrells JE, Van Twisk D, Thakar J, Benoit DSW. Evaluating side effects of nanoparticle-mediated siRNA delivery to mesenchymal stem cells using next generation sequencing and enrichment analysis. Bioeng Transl Med 2016; 1:193-206. [PMID: 27981244 PMCID: PMC5125403 DOI: 10.1002/btm2.10035] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2016] [Revised: 09/06/2016] [Accepted: 09/13/2016] [Indexed: 12/11/2022] Open
Abstract
RNA interference has immense potential to modulate cell functions. However, effective delivery of small interfering RNA (siRNA) while avoiding deleterious side effects has proven challenging. This study investigates both intended and unintended effects of diblock copolymer nanoparticle (NP) delivery of siRNA delivery to human mesenchymal stem cells (hMSC). Specifically, siRNA delivery was investigated at a range of NP‐siRNA:hMSC ratios with a focus on the effects of NP‐siRNA treatment on hMSC functions. Additionally, next generation RNA sequencing (RNAseq) was used with enrichment analysis to observe side effects in hMSC gene expression. Results show NP‐siRNA delivery is negatively correlated with hMSC density. However, higher NP‐siRNA:hMSC ratios increased cytotoxicity and decreased metabolic activity. hMSC proliferation was largely unaffected by NP‐siRNA treatment, except for a threefold reduction in hMSCs seeded at 4,000 cells/cm2. Flow cytometry reveals that apoptosis is a function of NP‐siRNA treatment time and seeding density; ∼14% of the treated hMSCs seeded at 8,000 cells/cm2 were annexin V+‐siRNA+ 24 hr after treatment, while 11% of the treated population was annexin V+‐siRNA−. RNAseq shows that NP‐siRNA treatment results in transcriptomic changes in hMSCs, while pathway analysis shows upregulation of apoptosis signaling and downregulation of metabolism, cell cycle, and DNA replication pathways, as corroborated by apoptosis, metabolism, and proliferation assays. Additionally, multiple innate immune signaling pathways such as toll‐like receptor, RIG‐I‐like receptor, and nuclear factor‐κB signaling pathways are upregulated. Furthermore, and consistent with traditional siRNA immune activation, cytokine–cytokine receptor signaling was also upregulated. Overall, this study provides insight into NP‐siRNA:hMSC ratios that are favorable for siRNA delivery. Moreover, NP‐siRNA delivery results in side effects across the hMSC transcriptome that suggest activation of the innate immunity that could alter MSC functions associated with their therapeutic potential.
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Affiliation(s)
- Dominic W Malcolm
- Dept. of Biomedical Engineering University of Rochester Rochester NY 14627; Center for Musculoskeletal Research, University of Rochester Rochester NY14642
| | - Janet E Sorrells
- Dept. of Biomedical Engineering University of Rochester Rochester NY 14627
| | - Daniel Van Twisk
- Dept. of Microbiology and Immunology University of Rochester Rochester NY 14627
| | - Juilee Thakar
- Dept. of Microbiology and Immunology University of Rochester Rochester NY 14627; Dept. of Biostatistics and Computational Biology University of Rochester Rochester NY 14642
| | - Danielle S W Benoit
- Dept. of Biomedical Engineering University of Rochester Rochester NY 14627; Center for Musculoskeletal Research, University of Rochester Rochester NY 14642; Dept. of Chemical Engineering University of Rochester Rochester NY 14627
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Lan Y, Theng S, Huang T, Choo K, Chen C, Kuo H, Chong K. Oncostatin M-Preconditioned Mesenchymal Stem Cells Alleviate Bleomycin-Induced Pulmonary Fibrosis Through Paracrine Effects of the Hepatocyte Growth Factor. Stem Cells Transl Med 2016; 6:1006-1017. [PMID: 28297588 PMCID: PMC5442768 DOI: 10.5966/sctm.2016-0054] [Citation(s) in RCA: 57] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 08/29/2016] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are widely considered for treatment of pulmonary fibrosis based on the anti‐inflammatory, antifibrotic, antiapoptotic, and regenerative properties of the cells. Recently, elevated levels of oncostatin M (OSM) have been reported in the bronchoalveolar lavage fluid of a pulmonary fibrosis animal model and in patients. In this work, we aimed to prolong engrafted MSC survival and to enhance the effectiveness of pulmonary fibrosis transplantation therapy by using OSM‐preconditioned MSCs. OSM‐preconditioned MSCs were shown to overexpress type 2 OSM receptor (gp130/OSMRβ) and exhibited high susceptibility to OSM, resulting in upregulation of the paracrine factor, hepatocyte growth factor (HGF). Moreover, OSM‐preconditioned MSCs enhanced cell proliferation and migration, attenuated transforming growth factor‐β1‐ or OSM‐induced extracellular matrix production in MRC‐5 fibroblasts through paracrine effects. In bleomycin‐induced lung fibrotic mice, transplantation of OSM‐preconditioned MSCs significantly improved pulmonary respiratory functions and downregulated expression of inflammatory factors and fibrotic factors in the lung tissues. Histopathologic examination indicated remarkable amelioration of the lung fibrosis. LacZ‐tagged MSCs were detected in the lung tissues of the OSM‐preconditioned MSC‐treated mice 18 days after post‐transplantation. Taken together, our data further demonstrated that HGF upregulation played an important role in mediating the therapeutic effects of transplanted OSM‐preconditioned MSCs in alleviating lung fibrosis in the mice. Stem Cells Translational Medicine2017;6:1006–1017
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Affiliation(s)
- Ying‐Wei Lan
- Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
| | - Si‐Min Theng
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
| | - Tsung‐Teng Huang
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
- Center for Molecular and Clinical Immunology, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
| | - Kong‐Bung Choo
- Department of Preclinical Sciences, Faculty of Medicine and Health Sciences, and Centre for Stem Cell Research, Universiti Tunku Abdul Rahman, Selangor, Malaysia
| | - Chuan‐Mu Chen
- Department of Life Sciences, National Chung Hsing University, Taichung, Taiwan, Republic of China
- Agricultural Biotechnology Center, National Chung Hsing University, Taichung, Taiwan, Republic of China
- Rong‐Hsing Translational Medicine Center, National Chung Hsing University, Taichung, Taiwan, Republic of China
| | - Han‐Pin Kuo
- Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Tao‐Yuan, Taiwan, Republic of China
- Department of Medicine, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
- Department of Internal Medicine, Chang Gung Memorial Hospital at Linkou, Tao‐Yuan, Taiwan, Republic of China
| | - Kowit‐Yu Chong
- Graduate Institute of Biomedical Sciences, Division of Biotechnology, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
- Department of Medical Biotechnology and Laboratory Science, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
- Department of Thoracic Medicine, Chang Gung Memorial Hospital at Linkou, Tao‐Yuan, Taiwan, Republic of China
- Molecular Medicine Research Center, College of Medicine, Chang Gung University, Tao‐Yuan, Taiwan, Republic of China
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LPS-TLR4 Pathway Mediates Ductular Cell Expansion in Alcoholic Hepatitis. Sci Rep 2016; 6:35610. [PMID: 27752144 PMCID: PMC5067590 DOI: 10.1038/srep35610] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 09/29/2016] [Indexed: 02/06/2023] Open
Abstract
Alcoholic hepatitis (AH) is the most severe form of alcoholic liver disease for which there are no effective therapies. Patients with AH show impaired hepatocyte proliferation, expansion of inefficient ductular cells and high lipopolysaccharide (LPS) levels. It is unknown whether LPS mediates ductular cell expansion. We performed transcriptome studies and identified keratin 23 (KRT23) as a new ductular cell marker. KRT23 expression correlated with mortality and LPS serum levels. LPS-TLR4 pathway role in ductular cell expansion was assessed in human and mouse progenitor cells, liver slices and liver injured TLR4 KO mice. In AH patients, ductular cell expansion correlated with portal hypertension and collagen expression. Functional studies in ductular cells showed that KRT23 regulates collagen expression. These results support a role for LPS-TLR4 pathway in promoting ductular reaction in AH. Maneuvers aimed at decreasing LPS serum levels in AH patients could have beneficial effects by preventing ductular reaction development.
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Cheung MB, Sampayo-Escobar V, Green R, Moore ML, Mohapatra S, Mohapatra SS. Respiratory Syncytial Virus-Infected Mesenchymal Stem Cells Regulate Immunity via Interferon Beta and Indoleamine-2,3-Dioxygenase. PLoS One 2016; 11:e0163709. [PMID: 27695127 PMCID: PMC5047639 DOI: 10.1371/journal.pone.0163709] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2016] [Accepted: 09/13/2016] [Indexed: 12/25/2022] Open
Abstract
Respiratory syncytial virus (RSV) has been reported to infect human mesenchymal stem cells (MSCs) but the consequences are poorly understood. MSCs are present in nearly every organ including the nasal mucosa and the lung and play a role in regulating immune responses and mediating tissue repair. We sought to determine whether RSV infection of MSCs enhances their immune regulatory functions and contributes to RSV-associated lung disease. RSV was shown to replicate in human MSCs by fluorescence microscopy, plaque assay, and expression of RSV transcripts. RSV-infected MSCs showed differentially altered expression of cytokines and chemokines such as IL-1β, IL6, IL-8 and SDF-1 compared to epithelial cells. Notably, RSV-infected MSCs exhibited significantly increased expression of IFN-β (~100-fold) and indoleamine-2,3-dioxygenase (IDO) (~70-fold) than in mock-infected MSCs. IDO was identified in cytosolic protein of infected cells by Western blots and enzymatic activity was detected by tryptophan catabolism assay. Treatment of PBMCs with culture supernatants from RSV-infected MSCs reduced their proliferation in a dose dependent manner. This effect on PBMC activation was reversed by treatment of MSCs with the IDO inhibitors 1-methyltryptophan and vitamin K3 during RSV infection, a result we confirmed by CRISPR/Cas9-mediated knockout of IDO in MSCs. Neutralizing IFN-β prevented IDO expression and activity. Treatment of MSCs with an endosomal TLR inhibitor, as well as a specific inhibitor of the TLR3/dsRNA complex, prevented IFN-β and IDO expression. Together, these results suggest that RSV infection of MSCs alters their immune regulatory function by upregulating IFN-β and IDO, affecting immune cell proliferation, which may account for the lack of protective RSV immunity and for chronicity of RSV-associated lung diseases such as asthma and COPD.
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Affiliation(s)
- Michael B. Cheung
- James A Haley Veterans Affairs Hospital, Tampa, Florida, United States of America
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, United States of America
| | - Viviana Sampayo-Escobar
- James A Haley Veterans Affairs Hospital, Tampa, Florida, United States of America
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, United States of America
| | - Ryan Green
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, United States of America
| | - Martin L. Moore
- Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia, United States of America
- Children’s Healthcare of Atlanta, Atlanta, Georgia, United States of America
| | - Subhra Mohapatra
- James A Haley Veterans Affairs Hospital, Tampa, Florida, United States of America
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, United States of America
| | - Shyam S. Mohapatra
- James A Haley Veterans Affairs Hospital, Tampa, Florida, United States of America
- Department of Molecular Medicine, University of South Florida Morsani College of Medicine, Tampa, Florida, United States of America
- University of South Florida College of Pharmacy, Tampa, Florida, United States of America
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Modulation of Immunoregulatory Properties of Mesenchymal Stromal Cells by Toll-Like Receptors: Potential Applications on GVHD. Stem Cells Int 2016; 2016:9434250. [PMID: 27738438 PMCID: PMC5050362 DOI: 10.1155/2016/9434250] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2016] [Accepted: 08/22/2016] [Indexed: 12/25/2022] Open
Abstract
In the last decade, the immunomodulatory properties of mesenchymal stromal cells (MSCs) have attracted a lot of attention, due to their potential applicability in the treatment of graft-versus-host disease (GVHD), a condition frequently associated with opportunistic infections. The present review addresses how Pathogen-Associated Molecular Patterns (PAMPS) modulate the immunosuppressive phenotype of human MSCs by signaling through Toll-like receptors (TLRs). Overall, we observed that regardless of the source tissue, human MSCs express TLR2, TLR3, TLR4, and TLR9. Stimulation of distinct TLRs on MSCs elicits distinct inflammatory signaling pathways, differentially influencing the expression of inflammatory factors and the ability of MSCs to suppress the proliferation of immune system cells. The capacity to enhance the immunosuppressive phenotype of MSCs through TLRs stimulation might be properly elucidated in order to improve the MSC-based immunotherapy against GVHD.
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Linard C, Strup-Perrot C, Lacave-Lapalun JV, Benderitter M. Flagellin preconditioning enhances the efficacy of mesenchymal stem cells in an irradiation-induced proctitis model. J Leukoc Biol 2016; 100:569-580. [PMID: 26992430 DOI: 10.1189/jlb.3a0915-393r] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2015] [Accepted: 02/29/2016] [Indexed: 12/12/2022] Open
Abstract
The success of mesenchymal stem cell transplantation for proctitis depends not only on cell donors but also on host microenvironmental factors, which play a major role in conditioning mesenchymal stem cell immunosuppressive action and repair. This study sought to determine if flagellin, a TLR5 ligand, can enhance the mesenchymal stem cell treatment efficacy in radiation-induced proctitis. With the use of a colorectal model of 27 Gy irradiation in rats, we investigated and compared the effects on immune capacity and remodeling at 28 d after irradiation of the following: 1) systemic mesenchymal stem cell (5 × 10(6)) administration at d 7 after irradiation, 2) administration of flagellin at d 3 and systemic mesenchymal stem cell administration at d 7, and 3) in vitro preconditioning of mesenchymal stem cells with flagellin, 24 h before their administration on d 7. The mucosal CD8(+) T cell population was normalized after treatment with flagellin-preconditioned mesenchymal stem cells or flagellin plus mesenchymal stem cells, whereas mesenchymal stem cells alone did not alter the radiation-induced elevation of CD8(+) T cell frequency. Mesenchymal stem cell treatment returned the irradiation-elevated frequency of CD25(+) cells in the mucosa-to-control levels, whereas both flagellin-preconditioned mesenchymal stem cell and flagellin-plus-mesenchymal stem cell treatment each significantly increased not only CD25(+) cell frequency but also forkhead box p3 and IL-2Rα expression. Specifically, IL-10 was overexpressed after flagellin-preconditioned mesenchymal stem cell treatment. Analysis of collagen expression showed that the collagen type 1/collagen type 3 ratio, an indicator of wound-healing maturation, was low in the irradiated and mesenchymal stem cell-treated groups and returned to the normal level only after the flagellin-preconditioned mesenchymal stem cell treatment. This was associated with a reduction in myofibroblast accumulation. In a proctitis model, flagellin-preconditioned mesenchymal stem cells improved colonic immune capacity and enhanced tissue remodeling.
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Affiliation(s)
- Christine Linard
- Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France
| | - Carine Strup-Perrot
- Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France
| | | | - Marc Benderitter
- Institut de Radioprotection et de Sûreté Nucléaire, Fontenay-aux-Roses, France
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No significant effects of Poly(I:C) on human umbilical cord-derived mesenchymal stem cells in the treatment of B6.MRL-Fas(lpr) mice. Curr Res Transl Med 2016; 64:55-60. [PMID: 27316386 DOI: 10.1016/j.retram.2016.03.002] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2015] [Accepted: 03/11/2016] [Indexed: 01/15/2023]
Abstract
OBJECTIVE Our study aimed to compare the curative effect and immunoregulation between MSCs activated by Poly(I:C) for 24hours and unactivated MSCs on lupus mice. MATERIALS AND METHODS MSCs were pretreated by Poly(I:C) at 50μg/mL for 24h. B6.MRL-Fas(lpr) mice were divided into UC-MSC treated group, FLS treated group, Poly(I:C) preconditioned MSC treated group (P-MSC) and untreated group randomly. All treated mice were infused with 1×10(6) MSCs or FLSs at the 24th week and were sacrificed 4 weeks later. The spleen weight, serum immunoglobulin G (IgG) levels, serum anti-double stranded DNA (anti-dsDNA) antibody levels, immune cell subsets, renal lesions and IgG deposition in the kidney were evaluated. The effects of two kinds of MSCs on the proliferation and apoptosis of CD4+ T cells were detected by flow cytometry. The TLR3 expression at protein level in MSCs was assessed with and without Poly(I:C) treatment. The expression of immunoregulatory factors were detected by qRT-PCR in different dose and duration of Poly(I:C). RESULT Poly(I:C) preconditioned MSCs had similar therapeutic effects in lupus mice compared with untreated MSCs in vivo. Furthermore, Poly(I:C) treated MSCs and untreated MSCs had comparable inhibitory effects on proliferation of T cells, and Poly(I:C) could enhance the expression of TLR3 at protein and mRNA level. Poly(I:C) could partly alter the mRNA levels of immunoregulatory factors, such as hepatocyte growth factor, transforming growth factor β1, vascular endothelial growth factor, but did not have significant changes in cyclooxygenase 2, interleukin 6, tumor necrosis factor α, indoleamine 2,3-dioxygenase, interferon γ and chemokine (C-C motif) ligand 2. CONCLUSION Our study did not find that Poly(I:C) treatment could enhance the therapeutic effect of MSCs in lupus mice in vivo.
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Abstract
Adult or somatic stem cells are tissue-resident cells with the ability to proliferate, exhibit self-maintenance as well as to generate new cells with the principal phenotypes of the tissue in response to injury or disease. Due to their easy accessibility and their potential use in regenerative medicine, adult stem cells raise the hope for future personalisable therapies. After infection or during injury, they are exposed to broad range of pathogen or damage-associated molecules leading to changes in their proliferation, migration and differentiation. The sensing of such damage and infection signals is mostly achieved by Toll-Like Receptors (TLRs) with Toll-like receptor 4 being responsible for recognition of bacterial lipopolysaccharides (LPS) and endogenous danger-associated molecular patterns (DAMPs). In this review, we examine the current state of knowledge on the TLR4-mediated signalling in different adult stem cell populations. Specifically, we elaborate on the role of TLR4 and its ligands on proliferation, differentiation and migration of mesenchymal stem cells, hematopoietic stem cells as well as neural stem cells. Finally, we discuss conceptual and technical pitfalls in investigation of TLR4 signalling in stem cells.
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Chiossone L, Conte R, Spaggiari GM, Serra M, Romei C, Bellora F, Becchetti F, Andaloro A, Moretta L, Bottino C. Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses. Stem Cells 2016; 34:1909-21. [PMID: 27015881 DOI: 10.1002/stem.2369] [Citation(s) in RCA: 145] [Impact Index Per Article: 16.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2015] [Revised: 02/07/2016] [Accepted: 03/02/2016] [Indexed: 12/16/2022]
Abstract
Mesenchymal stromal cells (MSCs) support hematopoiesis and exert immunoregulatory activities. Here, we analyzed the functional outcome of the interactions between MSCs and monocytes/macrophages. We showed that MSCs supported the survival of monocytes that underwent differentiation into macrophages, in the presence of macrophage colony-stimulating factor. However, MSCs skewed their polarization toward a peculiar M2-like functional phenotype (M(MSC) ), through a prostaglandin E2-dependent mechanism. M(MSC) were characterized by high expression of scavenger receptors, increased phagocytic capacity, and high production of interleukin (IL)-10 and transforming growth factor-β. These cytokines contributed to the immunoregulatory properties of M(MSC) , which differed from those of typical IL-4-induced macrophages (M2). In particular, interacting with activated natural killer (NK) cells, M(MSC) inhibited both the expression of activating molecules such as NKp44, CD69, and CD25 and the production of IFNγ, while M2 affected only IFNγ production. Moreover, M(MSC) inhibited the proliferation of CD8(+) T cells in response to allogeneic stimuli and induced the expansion of regulatory T cells (Tregs). Toll-like receptor engagement reverted the phenotypic and functional features of M(MSC) to those of M1 immunostimulatory/proinflammatory macrophages. Overall our data show that MSCs induce the generation of a novel type of alternatively activated macrophages capable of suppressing both innate and adaptive immune responses. These findings may help to better understand the role of MSCs in healthy tissues and inflammatory diseases including cancer, and provide clues for novel therapeutic approaches. Stem Cells 2016;34:1909-1921.
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Affiliation(s)
- Laura Chiossone
- Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy
| | - Romana Conte
- Laboratory of Immunology, IRCCS AOU San Martino-IST, Genoa, Italy
| | | | - Martina Serra
- Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy
| | - Cristina Romei
- Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy
| | - Francesca Bellora
- Department of Experimental Medicine, University of Genoa, Genoa, Italy
| | - Flavio Becchetti
- Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy
| | - Antonio Andaloro
- Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy
| | - Lorenzo Moretta
- Department of Immunology, Ospedale Pediatrico Bambino Gesù, Roma, Italy
| | - Cristina Bottino
- Laboratory of Clinical and Experimental Immunology, G. Gaslini Institute, Genoa, Italy.,Department of Experimental Medicine, University of Genoa, Genoa, Italy
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Najar M, Raicevic G, Fayyad-Kazan H, Bron D, Toungouz M, Lagneaux L. Mesenchymal stromal cells and immunomodulation: A gathering of regulatory immune cells. Cytotherapy 2016; 18:160-171. [PMID: 26794710 DOI: 10.1016/j.jcyt.2015.10.011] [Citation(s) in RCA: 191] [Impact Index Per Article: 21.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2015] [Revised: 10/01/2015] [Accepted: 10/13/2015] [Indexed: 12/13/2022]
Abstract
Because of their well-recognized immunomodulatory properties, mesenchymal stromal cells (MSCs) represent an attractive cell population for therapeutic purposes. In particular, there is growing interest in the use of MSCs as cellular immunotherapeutics for tolerance induction in allogeneic transplantations and the treatment of autoimmune diseases. However, multiple mechanisms have been identified to mediate the immunomodulatory effects of MSCs, sometimes with several ambiguities and inconsistencies. Although published studies have mainly reported the role of soluble factors, we believe that a sizeable cellular component plays a critical role in MSC immunomodulation. We refer to these cells as regulatory immune cells, which are generated from both the innate and adaptive responses after co-culture with MSCs. In this review, we discuss the nature and role of these immune regulatory cells as well as the role of different mediators, and, in particular, regulatory immune cell induction by MSCs through interleukin-10. Once induced, immune regulatory cells accumulate and converge their regulatory pathways to create a tolerogenic environment conducive for immunomodulation. Thus, a better understanding of these regulatory immune cells, in terms of how they can be optimally manipulated and induced, would be suitable for improving MSC-based immunomodulatory therapeutic strategies.
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Affiliation(s)
- Mehdi Najar
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium.
| | - Gordana Raicevic
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Hussein Fayyad-Kazan
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Dominique Bron
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Michel Toungouz
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
| | - Laurence Lagneaux
- Laboratory of Clinical Cell Therapy, Institut Jules Bordet, Université Libre de Bruxelles, Campus Erasme, Brussels, Belgium
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Leibacher J, Henschler R. Biodistribution, migration and homing of systemically applied mesenchymal stem/stromal cells. Stem Cell Res Ther 2016; 7:7. [PMID: 26753925 PMCID: PMC4709937 DOI: 10.1186/s13287-015-0271-2] [Citation(s) in RCA: 248] [Impact Index Per Article: 27.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem/stromal cells (MSCs) are increasingly used as an intravenously applied cellular therapeutic. They were found to be potent in situations such as tissue repair or severe inflammation. Still, data are lacking with regard to the biodistribution of MSCs, their cellular or molecular target structures, and the mechanisms by which MSCs reach these targets. This review discusses current hypotheses for how MSCs can reach tissue sites. Both preclinical and clinical studies using MSCs applied intravenously or intra-arterially are discussed in the context of our current understanding of how MSCs might work in physiological and pathological situations.
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Affiliation(s)
- Johannes Leibacher
- Institute of Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, University of Frankfurt, Frankfurt, Germany
| | - Reinhard Henschler
- Institute of Transfusion Medicine and Immune Hematology, German Red Cross Blood Donor Service, University of Frankfurt, Frankfurt, Germany. .,Blood Donor Center Zürich, Swiss Red Cross, Zürich, Switzerland.
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