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Waqar MA, Zaman M, Khan R, Shafeeq Ur Rahman M, Majeed I. Navigating the tumor microenvironment: mesenchymal stem cell-mediated delivery of anticancer agents. J Drug Target 2024; 32:624-634. [PMID: 38652480 DOI: 10.1080/1061186x.2024.2347356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2024] [Accepted: 04/21/2024] [Indexed: 04/25/2024]
Abstract
Scientific knowledge of cancer has advanced greatly throughout the years, with most recent studies findings includes many hallmarks that capture disease's multifaceted character. One of the novel approach utilised for the delivery of anti-cancer agents includes mesenchymal stem cell mediated drug delivery. Mesenchymal stem cells (MSCs) are non-haematopoietic progenitor cells that may be extracted from bone marrow, tooth pulp, adipose tissue and placenta/umbilical cord blood dealing with adult stem cells. MSCs are mostly involved in regeneration of tissue, they have also been shown to preferentially migrate to location of several types of tumour in-vivo. Usage of MSCs ought to improve both effectiveness and safety of anti-cancer drugs by enhancing delivery efficiency of anti-cancer therapies to tumour site. Numerous researches has demonstrated that various drugs, when delivered via mesenchymal stem cell mediated delivery can elicit anti-tumour effect of cells in cancers of breast cells and thyroid cells. MSCs have minimal immunogenicity because to lack of co-stimulatory molecule expression, which means there is no requirement for immunosuppression after allogenic transplantation. This current review elaborates recent advancements of mesenchyma stem cell mediated drug delivery of anti-cancer agents along with its mechanism and previously reported studies of drugs manufactured via this drug delivery system.
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Affiliation(s)
- Muhammad Ahsan Waqar
- Department of Pharmaceutics, Faculty of Pharmaceutical Sciences, Lahore University of Biological & Applied Sciences, Lahore, Pakistan
| | - Muhammad Zaman
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan
| | - Rabeel Khan
- Department of Pharmacy Practice, Faculty of Pharmaceutical Sciences, Lahore University of Biological & Applied Sciences, Lahore, Pakistan
| | | | - Imtiaz Majeed
- Faculty of Pharmaceutical Sciences, University of Central Punjab, Lahore, Pakistan
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Cassano JM, Leonard BC, Martins BC, Vapniarsky N, Morgan JT, Dow SW, Wotman KL, Pezzanite LM. Preliminary evaluation of safety and migration of immune activated mesenchymal stromal cells administered by subconjunctival injection for equine recurrent uveitis. Front Vet Sci 2023; 10:1293199. [PMID: 38162475 PMCID: PMC10757620 DOI: 10.3389/fvets.2023.1293199] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2023] [Accepted: 11/29/2023] [Indexed: 01/03/2024] Open
Abstract
Introduction Equine recurrent uveitis (ERU), an immune mediated disease characterized by repeated episodes of intra-ocular inflammation, affects 25% of horses in the USA and is the most common cause of glaucoma, cataracts, and blindness. Mesenchymal stromal cells (MSCs) have immunomodulatory properties, which are upregulated by preconditioning with toll-like receptor agonists. The objective was to evaluate safety and migration of TLR-3 agonist polyinosinic, polycytidylic acid (pIC)-activated MSCs injected subconjunctivally in healthy horses prior to clinical application in horses with ERU. We hypothesized that activated allogeneic MSCs injected subconjunctivally would not induce ocular or systemic inflammation and would remain in the conjunctiva for >14 days. Methods Bulbar subconjunctiva of two horses was injected with 10 × 106 pIC-activated (10 μg/mL, 2 h) GFP-labeled MSCs from one donor three times at two-week intervals. Vehicle (saline) control was injected in the contralateral conjunctiva. Horses received physical and ophthalmic exams [slit lamp biomicroscopy, rebound tonometry, fundic examination, and semiquantitative preclinical ocular toxicology scoring (SPOTS)] every 1-3 days. Systemic inflammation was assessed via CBC, fibrinogen, and serum amyloid A (SAA). Horses were euthanized 14 days following final injection. Full necropsy and histopathology were performed to examine ocular tissues and 36 systemic organs for MSC presence via IVIS Spectrum. Anti-GFP immunohistochemistry was performed on ocular tissues. Results No change in physical examinations was noted. Bloodwork revealed fibrinogen 100-300 mg/dL (ref 100-400) and SAA 0-25 μg/mL (ref 0-20). Ocular effects of the subjconjucntival injection were similar between MSC and control eyes on SPOTS grading system, with conjunctival hypermia, chemosis and ocular discharge noted bilaterally, which improved without intervention within 14 days. All other ocular parameters were unaffected throughout the study. Necropsy and histopathology revealed no evidence of systemic inflammation. Ocular histopathology was similar between MSC and control eyes. Fluorescent imaging analysis did not locate MSCs. Immunohistochemistry did not identify intact MSCs in the conjunctiva, but GFP-labeled cellular components were present in conjunctival phagocytic cells. Discussion Allogeneic pIC-activated conjunctival MSC injections were well tolerated. GFP-labeled tracking identified MSC components phagocytosed by immune cells subconjunctivally. This preliminary safety and tracking information is critical towards advancing immune conditioned cellular therapies to clinical trials in horses.
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Affiliation(s)
- Jennifer M. Cassano
- Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
- Department of Medicine and Epidemiology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Brian C. Leonard
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
- Department of Ophthalmology & Vision Science, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Bianca C. Martins
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Natalia Vapniarsky
- Veterinary Institute for Regenerative Cures, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California, Davis, Davis, CA, United States
| | - Joshua T. Morgan
- Department of Bioengineering, University of California, Riverside, Riverside, CA, United States
| | - Steven W. Dow
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
- Department of Microbiology, Immunology and Pathology, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
| | - Kathryn L. Wotman
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
| | - Lynn M. Pezzanite
- Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins, CO, United States
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Merlo B, Iacono E. Beyond Canine Adipose Tissue-Derived Mesenchymal Stem/Stromal Cells Transplantation: An Update on Their Secretome Characterization and Applications. Animals (Basel) 2023; 13:3571. [PMID: 38003188 PMCID: PMC10668816 DOI: 10.3390/ani13223571] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 11/14/2023] [Accepted: 11/17/2023] [Indexed: 11/26/2023] Open
Abstract
A dog is a valuable animal model and concomitantly a pet for which advanced therapies are increasingly in demand. The characteristics of mesenchymal stem/stromal cells (MSCs) have made cell therapy more clinically attractive. During the last decade, research on the MSC therapeutic effectiveness has demonstrated that tissue regeneration is primarily mediated by paracrine factors, which are included under the name of secretome. Secretome is a mixture of soluble factors and a variety of extracellular vesicles. The use of secretome for therapeutic purposes could have some advantages compared to cell-based therapies, such as lower immunogenicity and easy manufacturing, manipulation, and storage. The conditioned medium and extracellular vesicles derived from MSCs have the potential to be employed as new treatments in veterinary medicine. This review provides an update on the state-of-the-art characterization and applications of canine adipose tissue-derived MSC secretome.
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Affiliation(s)
- Barbara Merlo
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, Italy;
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, 40126 Bologna, Italy
| | - Eleonora Iacono
- Department of Veterinary Medical Sciences, University of Bologna, 40064 Bologna, Italy;
- Interdepartmental Centre for Industrial Research in Health Sciences and Technologies, University of Bologna, 40126 Bologna, Italy
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4
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Zhang R, Duan X, Liu Y, Xu J, Al-bashari AAG, Ye P, Ye Q, He Y. The Application of Mesenchymal Stem Cells in Future Vaccine Synthesis. Vaccines (Basel) 2023; 11:1631. [PMID: 38005963 PMCID: PMC10675160 DOI: 10.3390/vaccines11111631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/09/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023] Open
Abstract
Vaccines have significant potential in treating and/or preventing diseases, yet there remain challenges in developing effective vaccines against some diseases, such as AIDS and certain tumors. Mesenchymal stem cells (MSCs), a subset of cells with low immunogenicity, high proliferation potential, and an abundant source of extracellular vesicles (EVs), represent one of the novel and promising vaccine platforms. This review describes the unique features and potential mechanisms of MSCs as a novel vaccine platform. We also cover aspects such as the safety and stability of MSCs that warrant future in-depth studies.
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Affiliation(s)
- Rui Zhang
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Xingxiang Duan
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Ye Liu
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Jia Xu
- Australian Rivers Institute and School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia;
| | - Abdullkhaleg Ali Ghaleb Al-bashari
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Peng Ye
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Qingsong Ye
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Yan He
- Institute of Regenerative and Translational Medicine, Department of Stomatology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430030, China
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Burk J, Wittenberg-Voges L, Schubert S, Horstmeier C, Brehm W, Geburek F. Treatment of Naturally Occurring Tendon Disease with Allogeneic Multipotent Mesenchymal Stromal Cells: A Randomized, Controlled, Triple-Blinded Pilot Study in Horses. Cells 2023; 12:2513. [PMID: 37947591 PMCID: PMC10650642 DOI: 10.3390/cells12212513] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2023] [Revised: 10/13/2023] [Accepted: 10/19/2023] [Indexed: 11/12/2023] Open
Abstract
The treatment of tendinopathies with multipotent mesenchymal stromal cells (MSCs) is a promising option in equine and human medicine. However, conclusive clinical evidence is lacking. The purpose of this study was to gain insight into clinical treatment efficacy and to identify suitable outcome measures for larger clinical studies. Fifteen horses with early naturally occurring tendon disease were assigned to intralesional treatment with allogeneic adipose-derived MSCs suspended in serum or with serum alone through block randomization (dosage adapted to lesion size). Clinicians and horse owners remained blinded to the treatment during 12 months (seven horses per group) and 18 months (seven MSC-group and five control-group horses) of follow-up including clinical examinations and diagnostic imaging. Clinical inflammation, lameness, and ultrasonography scores improved more over time in the MSC group. The lameness score difference significantly improved in the MSC group compared with the control group after 6 months. In the MSC group, five out of the seven horses were free of re-injuries and back to training until 12 and 18 months. In the control group, three out of the seven horses were free of re-injuries until 12 months. These results suggest that MSCs are effective for the treatment of early-phase tendon disease and provide a basis for a larger controlled study.
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Affiliation(s)
- Janina Burk
- Institute of Physiology, Pathophysiology and Biophysics, University of Veterinary Medicine Vienna, Veterinaerplatz 1, 1210 Vienna, Austria
| | - Liza Wittenberg-Voges
- Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 9, 30559 Hannover, Germany;
| | - Susanna Schubert
- Institute of Human Genetics, University of Leipzig Medical Center, Philipp-Rosenthal-Strasse 55, 04103 Leipzig, Germany;
| | - Carolin Horstmeier
- Department for Horses, Veterinary Teaching Hospital, University of Leipzig, An den Tierkliniken 21, 04103 Leipzig, Germany; (C.H.); (W.B.)
| | - Walter Brehm
- Department for Horses, Veterinary Teaching Hospital, University of Leipzig, An den Tierkliniken 21, 04103 Leipzig, Germany; (C.H.); (W.B.)
| | - Florian Geburek
- Clinic for Horses, University of Veterinary Medicine Hannover, Foundation, Bünteweg 9, 30559 Hannover, Germany;
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Hwang J, Jang S, Kim C, Lee S, Jeong HS. Role of Stem Cell-Derived Exosomes and microRNAs in Spinal Cord Injury. Int J Mol Sci 2023; 24:13849. [PMID: 37762150 PMCID: PMC10530823 DOI: 10.3390/ijms241813849] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2023] [Revised: 08/30/2023] [Accepted: 09/06/2023] [Indexed: 09/29/2023] Open
Abstract
Neurological disorders represent a global health problem. Current pharmacological treatments often lead to short-term symptomatic relief but have dose-dependent side effects, such as inducing orthostatic arterial hypotension due to the blockade of alpha receptors, cardiotoxic effects due to impaired repolarization, and atrioventricular block and tachycardia, including ventricular fibrillation. These challenges have driven the medical community to seek effective treatments for this serious global health threat. Mesenchymal stem cells (MSCs) are pluripotent cells with anti-inflammatory, anti-apoptotic, and immunomodulatory properties, providing a promising alternative due to their ability to differentiate, favorable culture conditions, in vitro manipulation ability, and robust properties. Although MSCs themselves rarely differentiate into neurons at the site of injury after transplantation in vivo, paracrine factors secreted by MSCs can create environmental conditions for cell-to-cell communication and have shown therapeutic effects. Recent studies have shown that the pleiotropic effects of MSCs, particularly their immunomodulatory potential, can be attributed primarily to these paracrine factors. Exosomes derived from MSCs are known to play an important role in these effects. Many studies have evaluated the potential of exosome-based therapies for the treatment of various neurological diseases. In addition to exosomes, various miRNAs derived from MSCs have been identified to regulate genes and alleviate neuropathological changes in neurodegenerative diseases. This review explores the burgeoning field of exosome-based therapies, focusing on the effects of MSC-derived exosomes and exosomal miRNAs, and summarizes recent findings that shed light on the potential of exosomes in the treatment of neurological disorders. The insights gained from this review may pave the way for innovative and effective treatments for these complex conditions. Furthermore, we suggest the therapeutic effects of exosomes and exosomal miRNAs from MSCs, which have a rescue potential in spinal cord injury via diverse signaling pathways.
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Affiliation(s)
- Jinsu Hwang
- Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; (J.H.); (S.J.)
| | - Sujeong Jang
- Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; (J.H.); (S.J.)
| | - Choonghyo Kim
- Department of Neurosurgery, Kangwon National University School of Medicine, Chuncheon 24341, Republic of Korea;
| | - Sungjoon Lee
- Department of Neurosurgery, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul 06351, Republic of Korea;
| | - Han-Seong Jeong
- Department of Physiology, Chonnam National University Medical School, Hwasun 58128, Republic of Korea; (J.H.); (S.J.)
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Slovinska L, Harvanova D. The Role of Mesenchymal Stromal Cells and Their Products in the Treatment of Injured Spinal Cords. Curr Issues Mol Biol 2023; 45:5180-5197. [PMID: 37367078 DOI: 10.3390/cimb45060329] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2023] [Revised: 06/09/2023] [Accepted: 06/14/2023] [Indexed: 06/28/2023] Open
Abstract
Spinal cord injury (SCI) is a destructive condition that results in lasting neurological damage resulting in disruption of the connection between the central nervous system and the rest of the body. Currently, there are several approaches in the treatment of a damaged spinal cord; however, none of the methods allow the patient to return to the original full-featured state of life before the injury. Cell transplantation therapies show great potential in the treatment of damaged spinal cords. The most examined type of cells used in SCI research are mesenchymal stromal cells (MSCs). These cells are at the center of interest of scientists because of their unique properties. MSCs regenerate the injured tissue in two ways: (i) they are able to differentiate into some types of cells and so can replace the cells of injured tissue and (ii) they regenerate tissue through their powerful known paracrine effect. This review presents information about SCI and the treatments usually used, aiming at cell therapy using MSCs and their products, among which active biomolecules and extracellular vesicles predominate.
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Affiliation(s)
- Lucia Slovinska
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
- Department of Regenerative Medicine and Cell Therapy, Institute of Neurobiology Biomedical Research Center, Slovak Academy of Sciences, 040 01 Košice, Slovakia
| | - Denisa Harvanova
- Associated Tissue Bank, P.J. Šafárik University and L. Pasteur University Hospital, 040 01 Košice, Slovakia
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Pan Y, Wu W, Jiang X, Liu Y. Mesenchymal stem cell-derived exosomes in cardiovascular and cerebrovascular diseases: From mechanisms to therapy. Biomed Pharmacother 2023; 163:114817. [PMID: 37141733 DOI: 10.1016/j.biopha.2023.114817] [Citation(s) in RCA: 26] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/24/2023] [Accepted: 04/30/2023] [Indexed: 05/06/2023] Open
Abstract
Cardiovascular and cerebrovascular diseases (CVDs) remain an intractable problem and have high morbidity and mortality worldwide, as well as substantial health and economic burdens, representing an urgent clinical need. In recent years, the focus of research has shifted from the use of mesenchymal stem cells (MSCs) for transplantation to the use of their secretory exosomes (MSC-exosomes) for the treatment of numerous CVDs, including atherosclerosis, myocardial infarction (MI), heart failure (HF), ischemia/reperfusion (I/R), aneurysm, and stroke. MSCs are pluripotent stem cells with multiple differentiation pathways that exert pleiotropic effects by producing soluble factors, the most effective components of which are exosomes. MSC-exosomes are considered to be an excellent and promising cell-free therapy for CVDs due to their higher circulating stability, improved biocompatibility, reduced toxicity, and immunogenicity. In addition, exosomes play critical roles in repairing CVDs by inhibiting apoptosis, regulating inflammation, ameliorating cardiac remodeling, and promoting angiogenesis. Herein, we describe knowledge about the biological characteristics of MSC-exosomes, investigate the mechanism by which MSC-exosomes mediate therapeutic repair, and summarize recent advances in the efficacy of MSC-exosomes in CVDs, with a view toward future clinical applications.
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Affiliation(s)
- Yanhong Pan
- Department of Clinical Laboratory, The People's Hospital of Longhua Shenzhen, Shenzhen, Guangdong 518109, China.
| | - Weipeng Wu
- Department of Clinical Laboratory, Shenzhen Hospital of Southern University of Science and Technology, Shenzhen, Guangdong 518055, China
| | - Xiaoxin Jiang
- Department of Clinical Laboratory, The People's Hospital of Longhua Shenzhen, Shenzhen, Guangdong 518109, China
| | - Yunhong Liu
- Department of Clinical Laboratory, The People's Hospital of Longhua Shenzhen, Shenzhen, Guangdong 518109, China
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Tavasolian F, Inman RD. Biology and therapeutic potential of mesenchymal stem cell extracellular vesicles in axial spondyloarthritis. Commun Biol 2023; 6:413. [PMID: 37059822 PMCID: PMC10104809 DOI: 10.1038/s42003-023-04743-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Accepted: 03/21/2023] [Indexed: 04/16/2023] Open
Abstract
Axial spondyloarthritis (AxSpA) is a chronic, inflammatory, autoimmune disease that predominantly affects the joints of the spine, causes chronic pain, and, in advanced stages, may result in spinal fusion. Recent developments in understanding the immunomodulatory and tissue-differentiating properties of mesenchymal stem cell (MSC) therapy have raised the possibility of applying such treatment to AxSpA. The therapeutic effectiveness of MSCs has been shown in numerous studies spanning a range of diseases. Several studies have been conducted examining acellular therapy based on MSC secretome. Extracellular vesicles (EVs) generated by MSCs have been proven to reproduce the impact of MSCs on target cells. These EVs are associated with immunological regulation, tissue remodeling, and cellular homeostasis. EVs' biological effects rely on their cargo, with microRNAs (miRNAs) integrated into EVs playing a particularly important role in gene expression regulation. In this article, we will discuss the impact of MSCs and EVs generated by MSCs on target cells and how these may be used as unique treatment strategies for AxSpA.
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Affiliation(s)
- Fataneh Tavasolian
- Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada
| | - Robert D Inman
- Spondylitis Program, Division of Rheumatology, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada.
- Krembil Research Institute, University Health Network, Toronto, Ontario, Canada.
- Departments of Medicine and Immunology, University of Toronto, Toronto, Ontario, Canada.
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Sun X, Huang LY, Pan HX, Li LJ, Wang L, Pei GQ, Wang Y, Zhang Q, Cheng HX, He CQ, Wei Q. Bone marrow mesenchymal stem cells and exercise restore motor function following spinal cord injury by activating PI3K/AKT/mTOR pathway. Neural Regen Res 2022; 18:1067-1075. [PMID: 36254995 PMCID: PMC9827790 DOI: 10.4103/1673-5374.355762] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Although many therapeutic interventions have shown promise in treating spinal cord injury, focusing on a single aspect of repair cannot achieve successful and functional regeneration in patients following spinal cord injury . In this study, we applied a combinatorial approach for treating spinal cord injury involving neuroprotection and rehabilitation, exploiting cell transplantation and functional sensorimotor training to promote nerve regeneration and functional recovery. Here, we used a mouse model of thoracic contusive spinal cord injury to investigate whether the combination of bone marrow mesenchymal stem cell transplantation and exercise training has a synergistic effect on functional restoration. Locomotor function was evaluated by the Basso Mouse Scale, horizontal ladder test, and footprint analysis. Magnetic resonance imaging, histological examination, transmission electron microscopy observation, immunofluorescence staining, and western blotting were performed 8 weeks after spinal cord injury to further explore the potential mechanism behind the synergistic repair effect. In vivo, the combination of bone marrow mesenchymal stem cell transplantation and exercise showed a better therapeutic effect on motor function than the single treatments. Further investigations revealed that the combination of bone marrow mesenchymal stem cell transplantation and exercise markedly reduced fibrotic scar tissue, protected neurons, and promoted axon and myelin protection. Additionally, the synergistic effects of bone marrow mesenchymal stem cell transplantation and exercise on spinal cord injury recovery occurred via the PI3K/AKT/mTOR pathway. In vitro, experimental evidence from the PC12 cell line and primary cortical neuron culture also demonstrated that blocking of the PI3K/AKT/mTOR pathway would aggravate neuronal damage. Thus, bone marrow mesenchymal stem cell transplantation combined with exercise training can effectively restore motor function after spinal cord injury by activating the PI3K/AKT/mTOR pathway.
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Affiliation(s)
- Xin Sun
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Li-Yi Huang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Hong-Xia Pan
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Li-Juan Li
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Lu Wang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Gai-Qin Pei
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Yang Wang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Qing Zhang
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Hong-Xin Cheng
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Cheng-Qi He
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China
| | - Quan Wei
- Rehabilitation Medical Center and Institute of Rehabilitation Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan Province, China,Key Laboratory of Rehabilitation Medicine in Sichuan Province, Chengdu, Sichuan Province, China,Correspondence to: Quan Wei, .
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An Update on Applications of Cattle Mesenchymal Stromal Cells. Animals (Basel) 2022; 12:ani12151956. [PMID: 35953945 PMCID: PMC9367612 DOI: 10.3390/ani12151956] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/25/2022] [Revised: 07/27/2022] [Accepted: 07/29/2022] [Indexed: 12/14/2022] Open
Abstract
Simple Summary Among livestock species, cattle are crucially important for the meat and milk production industry. Cows can be affected by different pathologies, such as mastitis, endometritis and lameness, which can negatively affect either food production or reproductive efficiency. The use of mesenchymal stromal cells (MSCs) is a valuable tool both in the treatment of various medical conditions and in the application of reproductive biotechnologies. This review provides an update on state-of-the-art applications of bovine MSCs to clinical treatments and reproductive biotechnologies. Abstract Attention on mesenchymal stromal cells (MSCs) research has increased in the last decade mainly due to the promising results about their plasticity, self-renewal, differentiation potential, immune modulatory and anti-inflammatory properties that have made stem cell therapy more clinically attractive. Furthermore, MSCs can be easily isolated and expanded to be used for autologous or allogenic therapy following the administration of either freshly isolated or previously cryopreserved cells. The scientific literature on the use of stromal cells in the treatment of several animal health conditions is currently available. Although MSCs are not as widely used for clinical treatments in cows as for companion and sport animals, they have the potential to be employed to improve productivity in the cattle industry. This review provides an update on state-of-the-art applications of bovine MSCs to clinical treatments and reproductive biotechnologies.
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Peer BA, Bhat AR, Shabir U, Bharti MK, Bhat IA, Pandey S, Sharun K, Kumar R, Mathesh K, Saikumar G, Chandra V, Amarpal, Sharma GT. Comparative evaluation of fracture healing potential of differentiated and undifferentiated guinea pig and canine bone marrow-derived mesenchymal stem cells in a guinea pig model. Tissue Cell 2022; 76:101768. [DOI: 10.1016/j.tice.2022.101768] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/05/2022] [Revised: 02/22/2022] [Accepted: 02/22/2022] [Indexed: 11/26/2022]
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Mallis P, Chatzistamatiou T, Dimou Z, Sarri EF, Georgiou E, Salagianni M, Triantafyllia V, Andreakos E, Stavropoulos-Giokas C, Michalopoulos E. Mesenchymal stromal cell delivery as a potential therapeutic strategy against COVID-19: Promising evidence from in vitro results. World J Biol Chem 2022; 13:47-65. [PMID: 35432769 PMCID: PMC8966500 DOI: 10.4331/wjbc.v13.i2.47] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 12/28/2021] [Accepted: 03/06/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the coronavirus disease 2019 (COVID-19) pandemic, which was initiated in December 2019. COVID-19 is characterized by a low mortality rate (< 6%); however, this percentage is higher in elderly people and patients with underlying disorders. COVID-19 is characterized by mild to severe outcomes. Currently, several therapeutic strategies are evaluated, such as the use of anti-viral drugs, prophylactic treatment, monoclonal antibodies, and vaccination. Advanced cellular therapies are also investigated, thus representing an additional therapeutic tool for clinicians. Mesenchymal stromal cells (MSCs), which are known for their immunoregulatory properties, may halt the induced cytokine release syndrome mediated by SARS-CoV-2, and can be considered as a potential stem cell therapy. AIM To evaluate the immunoregulatory properties of MSCs, upon stimulation with COVID-19 patient serum. METHODS MSCs derived from the human Wharton's Jelly (WJ) tissue and bone marrow (BM) were isolated, cryopreserved, expanded, and defined according to the criteria outlined by the International Society for Cellular Therapies. Then, WJ and BM-MSCs were stimulated with a culture medium containing 15% COVID-19 patient serum, 1% penicillin-streptomycin, and 1% L-glutamine for 48 h. The quantification of interleukin (IL)-1 receptor a (Ra), IL-6, IL-10, IL-13, transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF)-a, fibroblast growth factor (FGF), platelet-derived growth factor (PDGF), and indoleamine-2,3-dioxygenase (IDO) was performed using commercial ELISA kits. The expression of HLA-G1, G5, and G7 was evaluated in unstimulated and stimulated WJ and BM-MSCs. Finally, the interactions between MSCs and patients' macrophages were established using co-culture experiments. RESULTS Thawed WJ and BM-MSCs exhibited a spindle-shaped morphology, successfully differentiated to "osteocytes", "adipocytes", and "chondrocytes", and in flow cytometric analysis were characterized by positivity for CD73, CD90, and CD105 (> 95%) and negativity for CD34, CD45, and HLA-DR (< 2%). Moreover, stimulated WJ and BM-MSCs were characterized by increased cytoplasmic granulation, in comparison to unstimulated cells. The HLA-G isoforms (G1, G5, and G7) were successfully expressed by the unstimulated and stimulated WJ-MSCs. On the other hand, only weak expression of HLA-G1 was identified in BM-MSCs. Stimulated MSCs secreted high levels of IL-1Ra, IL-6, IL-10, IL-13, TGF-β1, FGF, VEGF, PDGF, and IDO in comparison to unstimulated cells (P < 0.05) after 12 and 24 h. Finally, macrophages derived from COVID-19 patients successfully adapted the M2 phenotype after co-culturing with stimulated WJ and BM-MSCs. CONCLUSION WJ and BM-MSCs successfully produced high levels of immunoregulatory agents, which may efficiently modulate the over-activated immune responses of critically ill COVID-19 patients.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | | | - Zetta Dimou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Eirini-Faidra Sarri
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Eleni Georgiou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Maria Salagianni
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Vasiliki Triantafyllia
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | - Evangelos Andreakos
- Laboratory of Immunobiology, Center for Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
| | | | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, Athens 11527, Greece
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Kim GU, Sung SE, Kang KK, Choi JH, Lee S, Sung M, Yang SY, Kim SK, Kim YI, Lim JH, Seo MS, Lee GW. Therapeutic Potential of Mesenchymal Stem Cells (MSCs) and MSC-Derived Extracellular Vesicles for the Treatment of Spinal Cord Injury. Int J Mol Sci 2021; 22:13672. [PMID: 34948463 PMCID: PMC8703906 DOI: 10.3390/ijms222413672] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/14/2021] [Accepted: 12/18/2021] [Indexed: 12/15/2022] Open
Abstract
Spinal cord injury (SCI) is a life-threatening condition that leads to permanent disability with partial or complete loss of motor, sensory, and autonomic functions. SCI is usually caused by initial mechanical insult, followed by a cascade of several neuroinflammation and structural changes. For ameliorating the neuroinflammatory cascades, MSC has been regarded as a therapeutic agent. The animal SCI research has demonstrated that MSC can be a valuable therapeutic agent with several growth factors and cytokines that may induce anti-inflammatory and regenerative effects. However, the therapeutic efficacy of MSCs in animal SCI models is inconsistent, and the optimal method of MSCs remains debatable. Moreover, there are several limitations to developing these therapeutic agents for humans. Therefore, identifying novel agents for regenerative medicine is necessary. Extracellular vesicles are a novel source for regenerative medicine; they possess nucleic acids, functional proteins, and bioactive lipids and perform various functions, including damaged tissue repair, immune response regulation, and reduction of inflammation. MSC-derived exosomes have advantages over MSCs, including small dimensions, low immunogenicity, and no need for additional procedures for culture expansion or delivery. Certain studies have demonstrated that MSC-derived extracellular vesicles (EVs), including exosomes, exhibit outstanding chondroprotective and anti-inflammatory effects. Therefore, we reviewed the principles and patho-mechanisms and summarized the research outcomes of MSCs and MSC-derived EVs for SCI, reported to date.
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Affiliation(s)
- Gang-Un Kim
- Department of Orthopedic Surgery, Hanil General Hospital, 308 Uicheon-ro, Dobong-gu, Seoul 01450, Korea;
| | - Soo-Eun Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Kyung-Ku Kang
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Joo-Hee Choi
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Sijoon Lee
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Minkyoung Sung
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Seung Yun Yang
- Department of Biomaterials Science, Life and Industry Convergence Institute, Pusan National University, Miryang 50463, Korea;
| | - Seul-Ki Kim
- Efficacy Evaluation Team, Food Science R&D Center, KolmarBNH CO., LTD, 61Heolleungro 8-gil, Seocho-gu, Seoul 06800, Korea;
| | | | - Ju-Hyeon Lim
- New Drug Development Center, Osong Medical Innovation Foundation, Chungbuk 28160, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
| | - Min-Soo Seo
- Department of Laboratory Animal Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu 41061, Korea; (S.-E.S.); (K.-K.K.); (J.-H.C.); (S.L.); (M.S.)
| | - Gun Woo Lee
- Cellexobio, Co. Ltd., Daegu 42415, Korea;
- Department of Orthopedic Surgery, Yeungnam University College of Medicine, Yeungnam University Medical Center, 170 Hyonchung-ro, Namgu, Daegu 42415, Korea
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15
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Ghollasi M, Ghasembaglou S, Rahban D, Korani M, Motallebnezhad M, Asadi M, Zarredar H, Salimi A. Prospects for Manipulation of Mesenchymal Stem Cells in Tumor Therapy: Anti-Angiogenesis Property on the Spotlight. Int J Stem Cells 2021; 14:351-365. [PMID: 34456189 PMCID: PMC8611310 DOI: 10.15283/ijsc20146] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Revised: 06/01/2021] [Accepted: 06/16/2021] [Indexed: 11/10/2022] Open
Abstract
The interactions between the tumor microenvironment and the tumor cells confers a condition that accelerate or decelerate the development of tumor. Of these cells, mesenchymal stem cells (MSCs) have the potential to modulate the tumor cells. MSCs have been established with double functions, whereby contribute to a tumorigenic or anti-tumor setting. Clinical studies have indicated the potential of MSCs to be used as tool in treating the human cancer cells. One of the advantageous features of MSCs that make them as a well-suited tool for cancer therapy is the natural tumor-trophic migration potential. A key specification of the tumor development has been stablished to be angiogenesis. As a result, manipulation of angiogenesis has become an attractive approach for cancer therapy. This review article will seek to clarify the anti-angiogenesis strategy in modulating the MSCs to treat the tumor cells.
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Affiliation(s)
- Marzieh Ghollasi
- Department of Cell and Molecular Biology, Faculty of Biological Science, Kharazmi University, Tehran, Iran
| | - Shahram Ghasembaglou
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Dariush Rahban
- Department of Nanomedicine, School of Advanced Medical Technologies, Tehran University of Medical Sciences, Tehran, Iran
| | - Mohsen Korani
- Chemical Injuries Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Morteza Motallebnezhad
- Department of Immunology, Faculty of Medicine, Iran University of Medical Sciences, Tehran, Iran
| | - Milad Asadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Basic Oncology, Ege University, Institute of Health Sciences, Izmir, Turkey
| | - Habib Zarredar
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Science, Tabriz, Iran
| | - Ali Salimi
- Nanobiotechnology Research Center, Baqiyatallah University of Medical Sciences, Tehran, Iran
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Mallis P, Sokolis DP, Katsimpoulas M, Kostakis A, Stavropoulos-Giokas C, Michalopoulos E. Improved Repopulation Efficacy of Decellularized Small Diameter Vascular Grafts Utilizing the Cord Blood Platelet Lysate. Bioengineering (Basel) 2021; 8:118. [PMID: 34562940 PMCID: PMC8467559 DOI: 10.3390/bioengineering8090118] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Revised: 08/18/2021] [Accepted: 08/24/2021] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND The development of functional bioengineered small-diameter vascular grafts (SDVGs), represents a major challenge of tissue engineering. This study aimed to evaluate the repopulation efficacy of biological vessels, utilizing the cord blood platelet lysate (CBPL). METHODS Human umbilical arteries (hUAs, n = 10) were submitted to decellularization. Then, an evaluation of decellularized hUAs, involving histological, biochemical and biomechanical analysis, was performed. Wharton's Jelly (WJ) Mesenchymal Stromal Cells (MSCs) were isolated and characterized for their properties. Then, WJ-MSCs (1.5 × 106 cells) were seeded on decellularized hUAs (n = 5) and cultivated with (Group A) or without the presence of the CBPL, (Group B) for 30 days. Histological analysis involving immunohistochemistry (against Ki67, for determination of cell proliferation) and indirect immunofluorescence (against activated MAP kinase, additional marker for cell growth and proliferation) was performed. RESULTS The decellularized hUAs retained their initial vessel's properties, in terms of key-specific proteins, the biochemical and biomechanical characteristics were preserved. The evaluation of the repopulation process indicated a more uniform distribution of WJ-MSCs in group A compared to group B. The repopulated vascular grafts of group B were characterized by greater Ki67 and MAP kinase expression compared to group A. CONCLUSION The results of this study indicated that the CBPL may improve the repopulation efficacy, thus bringing the biological SDVGs one step closer to clinical application.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (C.S.-G.); (E.M.)
| | - Dimitrios P. Sokolis
- Laboratory of Biomechanics, Center for Experimental Surgery, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece;
| | - Michalis Katsimpoulas
- Center of Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (M.K.); (A.K.)
| | - Alkiviadis Kostakis
- Center of Experimental Surgery and Translational Research, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (M.K.); (A.K.)
| | - Catherine Stavropoulos-Giokas
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (C.S.-G.); (E.M.)
| | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 4 Soranou Ephessiou Street, 115 27 Athens, Greece; (C.S.-G.); (E.M.)
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17
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Tousian H, Razavi BM, Hosseinzadeh H. In search of elixir: Pharmacological agents against stem cell senescence. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2021; 24:868-880. [PMID: 34712416 PMCID: PMC8528253 DOI: 10.22038/ijbms.2021.51917.11773] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/12/2020] [Accepted: 03/02/2021] [Indexed: 12/13/2022]
Abstract
Stem cell senescence causes different complications. In addition to the aging phenomenon, stem cell senescence has been investigated in various concepts such as cancer, adverse drug effects, and as a limiting factor in cell therapy. This manuscript examines protective medicines and supplements which are capable of hindering stem cell senescence. We searched the databases such as EMBASE, PubMed, and Web of Science with the keywords "stem cell," "progenitor cell," "satellite," "senescence" and excluded the keywords "cancer," "tumor," "malignancy" and "carcinoma" until June 2020. Among these results, we chose 47 relevant studies. Our investigation indicates that most of these studies examined endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells, and a few others were about less-discussed types of stem cells such as cardiac stem cells, myeloblasts, and induced pluripotent stem cells. From another aspect, 17β-Estradiol, melatonin, metformin, rapamycin, coenzyme Q10, N-acetyl cysteine, and vitamin C were the most studied agents, while the main protective mechanism was through telomerase activity enhancement or oxidative damage ablation. Although many of these studies are in vitro, they are still worthwhile. Stem cell senescence in the in vitro expansion stage is an essential concern in clinical procedures of cell therapy. Moreover, in vitro studies are the first step for further in vivo and clinical studies. It is noteworthy to mention the fact that these protective agents have been used in the clinical setting for various purposes for a long time. Given that, we only need to examine their systemic anti-senescence effects and effective dosages.
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Affiliation(s)
- Hourieh Tousian
- Vice-chancellery of Food and Drug,Shahroud University of Medical Sciences, Shahroud, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran
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18
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Mallis P, Michalopoulos E, Chatzistamatiou T, Giokas CS. Interplay between mesenchymal stromal cells and immune system: clinical applications in immune-related diseases. EXPLORATION OF IMMUNOLOGY 2021. [DOI: 10.37349/ei.2021.00010] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Accepted: 06/07/2021] [Indexed: 11/08/2024]
Abstract
Mesenchymal stromal cells (MSCs) are a mesodermal stem cell population, with known self-renewal and multilineage differentiation properties. In the last century, MSCs have been widely used in regenerative medicine and tissue engineering approaches. MSCs initially were isolated from bone marrow aspirates, but currently have been identified in a great number of tissues of the human body. Besides their utilization in regenerative medicine, MSCs possess significant immunoregulatory/immunosuppressive properties, through interaction with the cells of innate and adaptive immunity. MSCs can exert their immunomodulatory properties with either cell-cell contact or via paracrine secretion of molecules, such as cytokines, growth factors and chemokines. Of particular importance, the MSCs’ immunomodulatory properties are explored as promising therapeutic strategies in immune-related disorders, such as autoimmune diseases, graft versus host disease, cancer. MSCs may also have an additional impact on coronavirus disease-19 (COVID-19), by attenuating the severe symptoms of this disorder. Nowadays, a great number of clinical trials, of MSC-mediated therapies are evaluated for their therapeutic potential. In this review, the current knowledge on cellular and molecular mechanisms involved in MSC-mediated immunomodulation were highlighted. Also, the most important aspects, regarding their potential application in immune-related diseases, will be highlighted. The broad application of MSCs has emerged their role as key immunomodulatory players, therefore their utilization in many disease situations is full of possibilities for future clinical treatment.
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Affiliation(s)
- Panagiotis Mallis
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Efstathios Michalopoulos
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
| | - Theofanis Chatzistamatiou
- Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece 2Histocompatibility & Immunogenetics Lab, Hellenic Cord Blood Bank, Biomedical Research Foundation Academy of Athens, 11527 Athens, Greece
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19
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Al Naem M, Bourebaba L, Kucharczyk K, Röcken M, Marycz K. Therapeutic mesenchymal stromal stem cells: Isolation, characterization and role in equine regenerative medicine and metabolic disorders. Stem Cell Rev Rep 2021; 16:301-322. [PMID: 31797146 DOI: 10.1007/s12015-019-09932-0] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSC) have become a popular treatment modality in equine orthopaedics. Regenerative therapies are especially interesting for pathologies like complicated tendinopathies of the distal limb, osteoarthritis, osteochondritis dissecans (OCD) and more recently metabolic disorders. Main sources for MSC harvesting in the horse are bone marrow, adipose tissue and umbilical cord blood. While the acquisition of umbilical cord blood is fairly easy and non-invasive, extraction of bone marrow and adipose tissue requires more invasive techniques. Characterization of the stem cells as a result of any isolation method, is also a crucial step for the confirmation of the cells' stemness properties; thus, three main characteristics must be fulfilled by these cells, namely: adherence, expression of a series of well-defined differentiation clusters as well as pluripotency. EVs, resulting from the paracrine action of MSCs, also play a key role in the therapeutic mechanisms mediated by stem cells; MSC-EVs are thus largely implicated in the regulation of proliferation, maturation, polarization and migration of various target cells. Evidence that EVs alone represent a complex network 0involving different soluble factors and could then reflect biophysical characteristics of parent cells has fuelled the importance of developing highly specific techniques for their isolation and analysis. All these aspects related to the functional and technical understanding of MSCs will be discussed and summarized in this review.
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Affiliation(s)
- Mohamad Al Naem
- Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany
| | - Lynda Bourebaba
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland.,International Institute of Translational Medicine, Jesionowa, 11, Malin, 55-114, Wisznia Mała, Poland
| | - Katarzyna Kucharczyk
- Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland
| | - Michael Röcken
- Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany
| | - Krzysztof Marycz
- Faculty of Veterinary Medicine, Equine Clinic - Equine Surgery, Justus-Liebig-University, 35392, Gießen, Germany. .,Department of Experimental Biology, Faculty of Biology and Animal Science, Wrocław University of Environmental and Life Sciences, Norwida 27B, 50-375, Wrocław, Poland. .,International Institute of Translational Medicine, Jesionowa, 11, Malin, 55-114, Wisznia Mała, Poland.
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20
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Khorsandi K, Hosseinzadeh R, Abrahamse H, Fekrazad R. Biological Responses of Stem Cells to Photobiomodulation Therapy. Curr Stem Cell Res Ther 2021; 15:400-413. [PMID: 32013851 DOI: 10.2174/1574888x15666200204123722] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2019] [Revised: 10/26/2019] [Accepted: 11/14/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Stem cells have attracted the researchers interest, due to their applications in regenerative medicine. Their self-renewal capacity for multipotent differentiation, and immunomodulatory properties make them unique to significantly contribute to tissue repair and regeneration applications. Recently, stem cells have shown increased proliferation when irradiated with low-level laser therapy or Photobiomodulation Therapy (PBMT), which induces the activation of intracellular and extracellular chromophores and the initiation of cellular signaling. The purpose of this study was to evaluate this phenomenon in the literature. METHODS The literature investigated the articles written in English in four electronic databases of PubMed, Scopus, Google Scholar and Cochrane up to April 2019. Stem cell was searched by combining the search keyword of "low-level laser therapy" OR "low power laser therapy" OR "low-intensity laser therapy" OR "photobiomodulation therapy" OR "photo biostimulation therapy" OR "LED". In total, 46 articles were eligible for evaluation. RESULTS Studies demonstrated that red to near-infrared light is absorbed by the mitochondrial respiratory chain. Mitochondria are significant sources of reactive oxygen species (ROS). Mitochondria play an important role in metabolism, energy generation, and are also involved in mediating the effects induced by PBMT. PBMT may result in the increased production of (ROS), nitric oxide (NO), adenosine triphosphate (ATP), and cyclic adenosine monophosphate (cAMP). These changes, in turn, initiate cell proliferation and induce the signal cascade effect. CONCLUSION The findings of this review suggest that PBMT-based regenerative medicine could be a useful tool for future advances in tissue engineering and cell therapy.
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Affiliation(s)
- Khatereh Khorsandi
- Department of Photodynamic, Medical Laser Research Center, YARA Institute, ACECR, Tehran, Iran;
and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Reza Hosseinzadeh
- Department of Medical Laser, Medical Laser Research Center, YARA Institute, ACECR, Tehran, Iran
| | - Heidi Abrahamse
- Laser Research Centre, NRF SARChI Chair: Laser Applications in Health, Faculty of Health Sciences, University of Johannesburg, Johannesburg, South Africa
| | - Reza Fekrazad
- Department of Periodontology, Dental Faculty - Radiation Sciences Research Center, Laser Research
Center in Medical Sciences, AJA University of Medical Sciences, Tehran, Iran,International Network for Photo Medicine and Photo Dynamic Therapy (INPMPDT), Universal Scientific Education and Research Network (USERN), Tehran, Iran
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21
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Cequier A, Sanz C, Rodellar C, Barrachina L. The Usefulness of Mesenchymal Stem Cells beyond the Musculoskeletal System in Horses. Animals (Basel) 2021; 11:ani11040931. [PMID: 33805967 PMCID: PMC8064371 DOI: 10.3390/ani11040931] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Revised: 03/21/2021] [Accepted: 03/22/2021] [Indexed: 12/11/2022] Open
Abstract
Simple Summary The main target of mesenchymal stem cell therapy in horses has long been the locomotor system, because these athletic animals commonly suffer from tendon and joint lesions. Originally, mesenchymal stem cells were thought to act by just differentiating into the cells of the injured tissue. However, these cells are also able to regulate and stimulate the body’s own repair mechanisms, opening the door to many applications in inflammatory and immune-mediated disorders in both animals and humans. In horses, beyond their traditional application in the musculoskeletal system, these cells have been studied for ophthalmologic pathologies such as corneal ulcers or immune-mediated processes, and for reproductive disorders such as endometritis/endometrosis. Their potential has been explored for equine pathologies very similar to those affecting people, such as asthma, metabolic syndrome, aberrant wound healing, or endotoxemia, as well as for equine-specific pathologies such as laminitis. Current evidence is still preliminary, and further research is needed to clarify different aspects, although research performed so far shows the promising potential of mesenchymal stem cells to treat a wide variety of equine pathologies, some of which are analogous to human disorders. Therefore, advancements in this path will be beneficial for both animals and people. Abstract The differentiation ability of mesenchymal stem cells (MSCs) initially raised interest for treating musculoskeletal injuries in horses, but MSC paracrine activity has widened their scope for inflammatory and immune-mediated pathologies in both equine and human medicine. Furthermore, the similar etiopathogenesis of some diseases in both species has advanced the concept of “One Medicine, One Health”. This article reviews the current knowledge on the use of MSCs for equine pathologies beyond the locomotor system, highlighting the value of the horse as translational model. Ophthalmologic and reproductive disorders are among the most studied for MSC application. Equine asthma, equine metabolic syndrome, and endotoxemia have been less explored but offer an interesting scenario for human translation. The use of MSCs in wounds also provides a potential model for humans because of the healing particularities in both species. High-burden equine-specific pathologies such as laminitis have been suggested to benefit from MSC-therapy, and MSC application in challenging disorders such as neurologic conditions has been proposed. The available data are preliminary, however, and require further development to translate results into the clinic. Nevertheless, current evidence indicates a significant potential of equine MSCs to enlarge their range of application, with particular interest in pathologies analogous to human conditions.
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Affiliation(s)
- Alina Cequier
- Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (A.C.); (C.R.)
| | - Carmen Sanz
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain;
| | - Clementina Rodellar
- Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (A.C.); (C.R.)
| | - Laura Barrachina
- Laboratorio de Genética Bioquímica LAGENBIO—Instituto de Investigación Sanitaria de Aragón (IIS)—Instituto Agroalimentario de Aragón (IA2), Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain; (A.C.); (C.R.)
- Servicio de Cirugía y Medicina Equina, Hospital Veterinario, Universidad de Zaragoza, C/Miguel Servet, 177, 50013 Zaragoza, Spain;
- Correspondence:
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22
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Connard SS, Linardi RL, Even KM, Berglund AK, Schnabel LV, Ortved KF. Effects of continuous passage on the immunomodulatory properties of equine bone marrow-derived mesenchymal stem cells in vitro. Vet Immunol Immunopathol 2021; 234:110203. [PMID: 33636546 DOI: 10.1016/j.vetimm.2021.110203] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2020] [Revised: 02/01/2021] [Accepted: 02/05/2021] [Indexed: 01/09/2023]
Abstract
BACKGROUND The immunomodulatory properties of mesenchymal stem cells (MSCs) have been studied extensively due to their increasing clinical application for tissue regeneration and repair following culture expansion. We have studied the effect of continuous passage on the immunomodulatory capacity of equine bone marrow-derived MSCs (BM-MSCs). Equine BM-MSCs were isolated and culture expanded to passage three, six, and nine (P3, P6, P9). Immunomodulatory properties of each passage were assessed using a T cell proliferation assay and cytokine synthesis following stimulation with interferon gamma (IFN-γ). RESULTS Equine BM-MSCs maintained their primary cell morphology and immunophenotype throughout all passages. T cell proliferation was suppressed by all passages of BM-MSCs, compared to peripheral blood mononuclear cells (PBMCs) alone. There was no significant difference in suppression of T cell proliferation between P3, P6, and P9 BM-MSCs. All passages of BM-MSCs significantly increased cytokine synthesis in response to stimulation with IFN-γ. There were no significant differences in production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) or regulate on activation, normal T cell expressed and secreted (RANTES) following stimulation with IFN-γ between P3, P6, and P9 BM-MSCs. P9 BM-MSCs had significantly increased production of tumor necrosis factor alpha (TNF-α), (IL-1β), and (IL-10) compared to P3 BM-MSCs. Additionally, there was a significant increase in production of (IL-8) in P6 and P9 BM-MSCs in comparison to P3 BM-MSCs. CONCLUSIONS Our findings demonstrate that culture expansion affects some of the immunomodulatory properties of BM-MSCs in vitro, which may suggest that MSCs isolated from a single collection of bone marrow may be culture expanded, but only those from lower passage numbers would be ideal for clinical application.
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Affiliation(s)
- Shannon S Connard
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Renata L Linardi
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Kayla M Even
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Alix K Berglund
- Department of Clinical Sciences, College of Veterinary Medicine and the Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States
| | - Lauren V Schnabel
- Department of Clinical Sciences, College of Veterinary Medicine and the Comparative Medicine Institute, North Carolina State University, Raleigh, NC, United States
| | - Kyla F Ortved
- Department of Clinical Studies, New Bolton Center, School of Veterinary Medicine, University of Pennsylvania, Philadelphia, PA, United States.
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23
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Jafari A, Rezaei-Tavirani M, Farhadihosseinabadi B, Zali H, Niknejad H. Human amniotic mesenchymal stem cells to promote/suppress cancer: two sides of the same coin. Stem Cell Res Ther 2021; 12:126. [PMID: 33579346 PMCID: PMC7881457 DOI: 10.1186/s13287-021-02196-x] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 01/27/2021] [Indexed: 02/08/2023] Open
Abstract
Cancer is a leading cause of death in both developed and developing countries, and because of population growth and aging, it is a growing medical burden worldwide. With robust development in medicine, the use of stem cells has opened new treatment modalities in cancer therapy. In adult stem cells, mesenchymal stem cells (MSCs) are showing rising promise in cancer treatment due to their unique properties. Among different sources of MSCs, human amniotic fluid/membrane is an attractive and suitable reservoir. There are conflicting opinions about the role of human amniotic membrane/fluid mesenchymal stem cells (hAMSCS/hAFMSCs) in cancer, as some studies demonstrating the anticancer effects of these cells and others suggesting their progressive effects on cancer. This review focuses on recent findings about the role of hAMSCs/hAFMSCs in cancer treatment and summarizes the suppressing as well as promoting effects of these cells on cancer progression and underling mechanisms.
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Affiliation(s)
- Ameneh Jafari
- Department of Basic Sciences, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
| | - Mostafa Rezaei-Tavirani
- Proteomics Research Center, Faculty of Paramedical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | | | - Hakimeh Zali
- Department of Tissue Engineering and Applied Cell Sciences, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Hassan Niknejad
- Department of Pharmacology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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24
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Liu L, Yuan Y, Zhang S, Xu J, Zou J. Osteoimmunological insights into the pathogenesis of ankylosing spondylitis. J Cell Physiol 2021; 236:6090-6100. [PMID: 33559242 DOI: 10.1002/jcp.30313] [Citation(s) in RCA: 44] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2020] [Revised: 01/10/2021] [Accepted: 01/25/2021] [Indexed: 12/12/2022]
Abstract
Ankylosing spondylitis (AS) is inflammatory arthritis predominantly affecting the spine, which is involved in the disorders of both immune and skeletal systems. The exact pathogenesis of AS is not fully understood. Osteoimmunology is a new subject of study in inflammatory arthritis, in particular the pathogenic events involved in the cross-regulation of both skeletal and immune systems. In this review, we discuss osteoimmunological and pathological changes of AS in the spine that are characterized by altered osteogenesis and osteolytic bone destruction, accompanied by the changes of the immune system. It was revealed that bone cells like mesenchymal stem cells, osteoblast, and osteoclast in crossing talking with immune cells such as T cells, B cells coregulate to the pathogenesis of AS. Further, an array of cytokines and molecules expressed by both skeletal and immune systems contribute to these complex interplays. Understanding the cellular and molecular mechanisms underlying the pathogenesis of AS will lay a foundation for the exploration of the potential new treatment to AS.
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Affiliation(s)
- Lifei Liu
- School of Kinesiology, Shanghai University of Sport, Shanghai, China.,Department of Rehabilitation, The People's Hospital of Liaoning Province, Shenyang, China
| | - Yu Yuan
- School of Sport and Health, Guangzhou Sport University, Guangzhou, China
| | - Shihua Zhang
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
| | - Jiake Xu
- School of Biomedical Sciences, University of Western Australia, Perth, Western Australia, Australia
| | - Jun Zou
- School of Kinesiology, Shanghai University of Sport, Shanghai, China
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25
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Gugjoo MB, Hussain S, Amarpal, Shah RA, Dhama K. Mesenchymal Stem Cell-Mediated Immuno-Modulatory and Anti- Inflammatory Mechanisms in Immune and Allergic Disorders. ACTA ACUST UNITED AC 2020; 14:3-14. [PMID: 32000656 PMCID: PMC7509741 DOI: 10.2174/1872213x14666200130100236] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 01/25/2020] [Accepted: 01/25/2020] [Indexed: 02/06/2023]
Abstract
Background: Mesenchymal Stem Cells (MSCs) are present in almost all the tissues of the body and act as the backbone of the internal tissue homeostasis. Among their various characteristic features, immuno-modulatory and/ anti-inflammatory properties play an important role in therapeutics. Objective: The current topic focuses on the characterization and immuno-modulatory and/ anti-inflammatory properties of MSCs. To present and discuss the current status of MSCs immuno-modulatory properties. Methods: Available literature on MSCs properties and patents have been detailed, critically interpreted, and discussed based upon available literature. The main focus has been on their characteristic immuno-modulatory and anti-inflammatory properties though some of the basic characterization markers have also been detailed. The databases searched for the literature include PubMed, Med Line, PubMed Central, Science Direct and a few other scientific databases. Results: MSCs are present in a very limited concentration in the tissues, and as such their culture expansion becomes imperative. MSCs immuno-modulatory and anti-inflammatory roles are achieved through direct cell-cell contact and / by the release of certain factors. Such properties are controlled by micro-environment upon which currently very limited control can be exerted. Besides, further insights in the xeno-protein free culture media as against the fetal bovine serum is required. Conclusion: MSCs have been well-isolated, cultured and characterized from numerous tissues of the body. The majority of the studies have shown MSCs as immuno-compromised with immunomodulatory and / or anti-inflammatory properties except some of the latest studies that have failed to achieve the desired results and thus, demand further research. Further research is required in the area to translate the results into clinical application.
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Affiliation(s)
- Mudasir B Gugjoo
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Shahid Hussain
- Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Amarpal
- Division of Surgery, ICAR-Indian Veterinary Research Institute, Izatnagar, Bareilly, 243 122, Uttar Pradesh, India
| | - Riaz A Shah
- Divison of Animal Biotechnology, Faculty of Veterinary Sciences and Animal Husbandry, SKUAST, Shuhama, Srinagar-190006, Jammu and Kashmir, India
| | - Kuldeep Dhama
- Division of Pathology, ICARIndian Veterinary Research Institute, Izatnagar, Bareilly, 243 122, Uttar Pradesh, India
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26
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Cai Z, Wu B, Ye G, Liu W, Chen K, Wang P, Xie Z, Li J, Zheng G, Yu W, Su Z, Lin J, Wu Y, Shen H. Enhanced Osteogenic Differentiation of Human Bone Marrow Mesenchymal Stem Cells in Ossification of the Posterior Longitudinal Ligament Through Activation of the BMP2-Smad1/5/8 Pathway. Stem Cells Dev 2020; 29:1567-1576. [PMID: 33096960 DOI: 10.1089/scd.2020.0117] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Ossification of the posterior longitudinal ligament (OPLL) is characterized by ectopic OPLL. To date, the specific molecular pathogenesis of OPLL has not been clearly elucidated. In this study, bone marrow-derived mesenchymal stem cells obtained from healthy donors (HD-MSCs) and patients with OPLL (OPLL-MSCs) were cultured in osteogenic differentiation medium for 21 days. The osteogenic differentiation capacity was determined by alizarin red S (ARS) and alkaline phosphatase (ALP) assays. Gene expression levels of osteoblastic markers were measured by quantitative reverse transcription-polymerase chain reaction. Protein levels of related genes and the activation of related signaling pathways were measured by western blotting. LDN193189 was used to inhibit the Smad1/5/8 pathway, and small interfering RNA was used to regulate BMP2 expression. Our results showed that the OPLL-MSCs had stronger ARS staining and ALP activity and higher expression of RUNX2, Osterix, and OCN than the HD-MSCs. During osteogenic differentiation, the Smad1/5/8 pathway was overactivated in the OPLL-MSCs, and LDN193189 inhibition reversed the enhanced osteogenic ability of these cells. Besides, BMP2 was upregulated in the OPLL-MSCs. After BMP2 knockdown, the abnormal osteogenic differentiation of OPLL-MSCs was rescued. Thus, abnormal activation of the BMP2-Smad1/5/8 pathway induces enhanced osteogenic differentiation of OPLL-MSCs compared with HD-MSCs. These findings reveal a mechanism of pathological osteogenesis in OPLL and provide a new perspective on inhibiting pathological osteogenesis by regulating BMP2.
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Affiliation(s)
- Zhaopeng Cai
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Boyang Wu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Guiwen Ye
- Department of Orthopedics, and Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Wenjie Liu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Keng Chen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Zhongyu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jinteng Li
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Wenhui Yu
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Zepeng Su
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Jiajie Lin
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China
| | - Yanfeng Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
| | - Huiyong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen, China.,Department of Orthopedics, and Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
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27
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Ren Z, Qi Y, Sun S, Tao Y, Shi R. Mesenchymal Stem Cell-Derived Exosomes: Hope for Spinal Cord Injury Repair. Stem Cells Dev 2020; 29:1467-1478. [PMID: 33045910 DOI: 10.1089/scd.2020.0133] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Spinal cord injury (SCI) is a devastating medical condition with profound social and economic impacts. Although research is ongoing, current treatment options are limited and do little to restore functionality. However, recent studies suggest that mesenchymal stem cell-derived exosomes (MSC-exosomes) may hold the key to exciting new treatment options for SCI patients. MSCs are self-renewing multipotent stem cells with multi-directional differentiation and can secrete a large number of exosomes (vesicles secreted into the extracellular environment through endocytosis, called MSC-exosomes). These MSC-exosomes play a critical role in repairing SCI through promoting angiogenesis and axonal growth, regulating inflammation and the immune response, inhibiting apoptosis, and maintaining the integrity of the blood-spinal cord barrier. Furthermore, they can be utilized to transport genetic material or drugs to target cells, and their relatively small size makes them able to permeate the blood-brain barrier. In this review, we summarize recent advances in MSC-exosome themed SCI treatments and cell-free therapies to better understand this newly emerging methodology.
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Affiliation(s)
- Zhihua Ren
- Department of Basic Medical Sciences, College of Veterinary Medicine, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Yaan, China
| | - Yao Qi
- Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Yaan, China
| | - Siyuan Sun
- Department of Basic Medical Sciences, College of Veterinary Medicine, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.,Department of Orthopedics, National Clinical Research Center for Geriatric Diseases, Xuanwu Hospital, Capital Medical University, Beijing, China
| | - Yuanyuan Tao
- Department of Basic Medical Sciences, College of Veterinary Medicine, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA.,Key Laboratory of Animal Disease and Human Health of Sichuan Province, College of Veterinary Medicine, Sichuan Agricultural University, Yaan, China
| | - Riyi Shi
- Department of Basic Medical Sciences, College of Veterinary Medicine, Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, USA
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28
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Pham PV, Vu NB. Off-the-shelf mesenchymal stem cells from human umbilical cord tissue can significantly improve symptoms in COVID-19 patients: An analysis of evidential relations. World J Stem Cells 2020; 12:721-730. [PMID: 32952854 PMCID: PMC7477657 DOI: 10.4252/wjsc.v12.i8.721] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/06/2020] [Revised: 05/21/2020] [Accepted: 08/01/2020] [Indexed: 02/06/2023] Open
Abstract
Coronavirus disease-2019 (COVID-19) has affected more than 200 countries worldwide. This disease has hugely affected healthcare systems as well as the economy to an extent never seen before. To date, COVID-19 infection has led to about 165000 deaths in 150 countries. At present, there is no specific drug or efficient treatment for this disease. In this analysis based on evidential relationships of the biological characteristics of MSCs, especially umbilical cord (UC)-derived MSCs as well as the first clinical trial using MSCs for COVID-19 treatment, we discuss the use of UC-MSCs to improve the symptoms of COVID-19 in patients.
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Affiliation(s)
- Phuc Van Pham
- Stem Cell Institute, University of Science, Ho Chi Minh 08000, Viet Nam
- Vietnam National University, Ho Chi Minh 08000, Viet Nam
| | - Ngoc Bich Vu
- Stem Cell Institute, University of Science, Ho Chi Minh 08000, Viet Nam
- Vietnam National University, Ho Chi Minh 08000, Viet Nam
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29
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Tousian H, Razavi BM, Hosseinzadeh H. Looking for immortality: Review of phytotherapy for stem cell senescence. IRANIAN JOURNAL OF BASIC MEDICAL SCIENCES 2020; 23:154-166. [PMID: 32405357 PMCID: PMC7211350 DOI: 10.22038/ijbms.2019.40223.9522] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
In this paper, we discussed natural agents with protective effects against stem cell senescence. Different complications have been observed due to stem cell senescence and the most important of them is "Aging". Senescent cells have not normal function and their secretary inflammatory factors induce chronic inflammation in body which causes different pathologies. Stem cell senescence also has been investigated in different diseases or as drug adverse effects. We searched databases such as Embase, Pubmed and Web of Science with keywords "stem cell", "progenitor cell", "satellite", "senescence" and excluded keywords "cancer", "tumor", "malignancy" and "carcinoma" without time limitation until May 2019. Among them we chose 52 articles that have investigated protective effects of natural agents (extracts or molecules) against cellular senescence in different kind of adult stem cells. Most of these studies were in endothelial progenitor cells, hematopoietic stem cells, mesenchymal stem cells, adipose-derived stem cells and few were about other kinds of stem cells. Most studied agents were resveratrol and ginseng which are also commercially available as supplement. Most protective molecular targets were telomerase and anti-oxidant enzymes to preserve genome integrity and reduce senescence-inducing signals. Due to the safe and long history of herbal usage in clinic, phytotherapy can be used for preventing stem cell senescence and their related complication. Resveratrol and ginseng can be the first choice for this aim due to their protective mechanisms in various kinds of stem cells and their long term clinical usage.
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Affiliation(s)
- Hourieh Tousian
- Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Bibi Marjan Razavi
- Targeted Drug Delivery Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hossein Hosseinzadeh
- Pharmaceutical Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad, Iran.,Department of Pharmacodynamics and Toxicology, School of Pharmacy, Mashhad University of Medical Sciences, Mashhad, Iran
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30
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Lu XX, Zhao SZ. Gene-based Therapeutic Tools in the Treatment of Cornea Disease. Curr Gene Ther 2020; 19:7-19. [PMID: 30543166 DOI: 10.2174/1566523219666181213120634] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2018] [Revised: 11/23/2018] [Accepted: 12/11/2018] [Indexed: 02/07/2023]
Abstract
BACKGROUND As one of the main blinding ocular diseases, corneal blindness resulted from neovascularization that disrupts the angiogenic privilege of corneal avascularity. Following neovascularization, inflammatory cells are infiltrating into cornea to strengthen corneal injury. How to maintain corneal angiogenic privilege to treat corneal disease has been investigated for decades. METHODOLOGY Local administration of viral and non-viral-mediated anti-angiogenic factors reduces angiogenic protein expression in situ with limited or free of off-target effects upon gene delivery. Recently, Mesenchymal Stem Cells (MSCs) have been studied to treat corneal diseases. Once MSCs are manipulated to express certain genes of interest, they could achieve superior therapeutic efficacy after transplantation. DISCUSSION In the text, we first introduce the pathological development of corneal disease in the aspects of neovascularization and inflammation. We summarize how MSCs become an ideal candidate in cell therapy for treating injured cornea, focusing on cell biology, property and features. We provide an updated review of gene-based therapies in animals and preclinical studies in the aspects of controlling target gene expression, safety and efficacy. Gene transfer vectors are potent to induce candidate protein expression. Delivered by vectors, MSCs are equipped with certain characters by expressing a protein of interest, which facilitates better for MSC-mediated therapeutic intervention for the treatment of corneal disease. CONCLUSION As the core of this review, we discuss how MSCs could be engineered to be vector system to achieve enhanced therapeutic efficiency after injection.
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Affiliation(s)
- Xiao-Xiao Lu
- Tianjin Medical University Eye Hospital and Institute, Tianjin 300384, China
| | - Shao-Zhen Zhao
- Tianjin Medical University Eye Hospital and Institute, Tianjin 300384, China
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31
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Jose J, George T, Thomas AM. Regulation of Stem Cell-Based Research in India in Comparison with the US, EU and other Asian Countries: Current Issues and Future Perspectives. Curr Stem Cell Res Ther 2020; 15:492-508. [PMID: 32250233 DOI: 10.2174/1574888x15666200402134750] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2019] [Revised: 11/20/2019] [Accepted: 11/29/2019] [Indexed: 11/22/2022]
Abstract
Stem cell therapy is applicable for repair and replacement of damaged cells and tissues. Apart from transplanting cells to the body, the stem cell therapy directs them to grow new and healthy tissues. Stem cells in the area of regenerative medicines hold tremendous promise that may help to regenerate the damaged tissues and heal various diseases like multiple sclerosis, heart diseases, Parkinson's disease, and so on. To prove the safety, efficacy, and for the requirement of a licence for manufacturing and sale, all the stem cell therapies should pass the required criteria and undergo certain examinations of the regulatory agencies. The regulatory authorities review the manufacturing procedures of products to assure its purity and potency. This review summarizes the comparative critical evaluations of existing regulations and developments on the stem cells research in India, USA, EU and Asian regions and also discusses the challenges that have to be overcome and the important points that should be understood to position India as a source of the perspective nation in stem cells around the world.
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Affiliation(s)
- Jobin Jose
- Department of Pharmaceutical Regulatory Affairs and Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE Deemed to be University, Paneer, Mangalore 575018, Karnataka, India
| | - Teena George
- Department of Pharmaceutical Regulatory Affairs and Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE Deemed to be University, Paneer, Mangalore 575018, Karnataka, India
| | - Aaron M Thomas
- Department of Pharmaceutical Regulatory Affairs and Pharmaceutics, NGSM Institute of Pharmaceutical Sciences, NITTE Deemed to be University, Paneer, Mangalore 575018, Karnataka, India
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32
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Gugjoo MB, Amarpal, Abdelbaset-Ismail A, Aithal HP, Kinjavdekar P, Kumar GS, Sharma GT. Allogeneic mesenchymal stem cells and growth factors in gel scaffold repair osteochondral defect in rabbit. Regen Med 2020; 15:1261-1275. [PMID: 32154762 DOI: 10.2217/rme-2018-0138] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Aim: An attempt was made to improve osteochondral healing with allogeneic mesenchymal stem cells (MSCs) along with certain growth factors. Materials & methods: Induced knee osteochondral defects were filled as: phosphate buffer saline (group A); MSCs in collagen gel (group B); group B plus insulin like growth factor-1 (group C); group C plus transforming growth factor β-1 (group D). Results: Gross and scanning electron microscopy showed superior morphology and surface architecture of the healed tissue in groups D and C. Histologically, group D revealed hyaline cartilage characteristic features followed in order by group C and group B. In all treatment groups, chondrogenic matrix, collagen II2B (col II 2B) and aggrecan were secreted. Conclusion: Combined use of MSCs and growth factors could accelerate osteochondral healing.
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Affiliation(s)
- Mudasir Bashir Gugjoo
- Division of Surgery, Indian Veterinary Research Institute (IVRI), Izzatnagar, India.,Division of Veterinary Clinical Complex, Faculty of Veterinary Sciences & Animal Husbandry, SKUAST-K, Shuhama, India
| | - Amarpal
- Division of Surgery, Indian Veterinary Research Institute, Izzatnagar, India
| | - Ahmed Abdelbaset-Ismail
- Stem Cell Institute at James Graham Brown Cancer Center, University of Louisville, Louisville, KY 40202, USA.,Radiology & Anesthesiology Department, Faculty of Veterinary Medicine, Zagazig University, El-Sharkia, Zagazig, Egypt
| | - Hari Prasad Aithal
- Division of Surgery, Indian Veterinary Research Institute, Izzatnagar, India
| | - Prakash Kinjavdekar
- Division of Surgery, Indian Veterinary Research Institute, Izzatnagar, India
| | - Gutulla Sai Kumar
- Division of Pathology, Indian Veterinary Research Institute, Izzatnagar, India
| | - Gutulla Taru Sharma
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Izzatnagar, India
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33
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Gugjoo MB, Fazili MUR, Gayas MA, Ahmad RA, Dhama K. Animal mesenchymal stem cell research in cartilage regenerative medicine - a review. Vet Q 2020; 39:95-120. [PMID: 31291836 PMCID: PMC8923021 DOI: 10.1080/01652176.2019.1643051] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Healing of articular cartilage is a major clinical challenge as it also lacks a direct vasculature and nerves, and carries a limited number of resident chondrocytes that do not proliferate easily. Damaged articular cartilages are usually replaced by fibrocartilages, which are mechanically and structurally weaker and less resilient. Regenerative medicine involving stem cells is considered to have a definitive potential to overcome the limitations associated with the currently available surgical methods of cartilage repair. Among various stem cell types, mesenchymal stem cells (MSCs) are preferred for clinical applications. These cells can be readily derived from various sources and have the ability to trans-differentiate into various tissue-specific cells, including those of the cartilage by the process of chondrogenesis. Compared to embryonic or induced pluripotent stem cells (iPSCs), no ethical or teratogenic issues are associated with MSCs. These stem cells are being extensively evaluated for the treatment of joint affections and the results appear promising. Unlike human medicine, in veterinary medicine, the literature on stem cell research for cartilage regeneration is limited. This review, therefore, aims to comprehensively discuss the available literature and pinpoint the achievements and limitations associated with the use of MSCs for articular cartilage repair in animal species.
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Affiliation(s)
| | | | | | - Raja Aijaz Ahmad
- Division of Veterinary Clinical Complex, FVSc and AH, SKUAST , Srinagar , India
| | - Kuldeep Dhama
- Division of Pathology, Indian Veterinary Research Institute , Bareilly, India
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MacDonald ES, Barrett JG. The Potential of Mesenchymal Stem Cells to Treat Systemic Inflammation in Horses. Front Vet Sci 2020; 6:507. [PMID: 32039250 PMCID: PMC6985200 DOI: 10.3389/fvets.2019.00507] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Accepted: 12/20/2019] [Indexed: 12/13/2022] Open
Abstract
One hallmark of mesenchymal stem cells (MSCs) is the ability to differentiate into multiple tissue types which assists in tissue regeneration. Another hallmark of MSCs is their potent anti-inflammatory and immunomodulatory properties and the potential to treat inflammatory, immune-mediated, and ischemic conditions. In equine practice, MSCs have shown efficacy in the treatment of musculoskeletal disorders such as tendinopathy, meniscal tears and cartilage injury. However, there are many equine disease processes and conditions that may benefit from the immunomodulatory properties of MSCs. Examples include conditions associated with overwhelming acute inflammatory response such as systemic inflammatory response syndrome to chronic diseases characterized by a prolonged low level of inflammation such as equine asthma and recurrent uveitis. For the acute inflammatory response processes, there is often high morbidity and mortality with no effective immunomodulatory treatment to prevent the overwhelming synthesis of proinflammatory mediators. For chronic inflammatory disease processes, frequently long-term corticosteroid treatment is the therapeutic mainstay, with serious potential complications. Thus, there is an unmet need for alternative anti-inflammatory treatments for both acute and chronic illnesses in horses. While MSCs show promise for such conditions, much research is needed before a clinically safe and effective treatment will be available. Optimal MSC tissue source, patient vs. donor source (autologous vs. allogeneic) and cell growth conditions need to be determined for each problem. For immediate use, allogeneic MSC treatments is preferable, but immune tolerance and adequate safety require further study. MSC collection and cryopreservation from horses before they are injured or ill, whether from umbilical cord tissue, bone marrow or adipose might become more widespread. Once these fundamental approaches to treating specific diseases with MSCs are determined, the route of administration, dose and timing of administration also need to be studied. To provide a framework for development of MSC immunomodulatory treatments, this article reviews the current understanding of equine MSC anti-inflammatory and immunomodulatory properties and proposes how MSC therapy may be further developed to treat acute onset systemic inflammatory processes and chronic inflammatory diseases.
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Affiliation(s)
- Elizabeth S MacDonald
- Marion duPont Scott Equine Medical Center, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, United States
| | - Jennifer G Barrett
- Marion duPont Scott Equine Medical Center, Virginia Maryland College of Veterinary Medicine, Virginia Tech, Leesburg, VA, United States
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Mahdavi Gorabi A, Banach M, Reiner Ž, Pirro M, Hajighasemi S, Johnston TP, Sahebkar A. The Role of Mesenchymal Stem Cells in Atherosclerosis: Prospects for Therapy via the Modulation of Inflammatory Milieu. J Clin Med 2019; 8:1413. [PMID: 31500373 PMCID: PMC6780166 DOI: 10.3390/jcm8091413] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 09/02/2019] [Accepted: 09/04/2019] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a chronic, inflammatory disease that mainly affects the arterial intima. The disease is more prevalent in middle-age and older individuals with one or more cardiovascular risk factors, including dyslipidemia, hypertension, diabetes, smoking, obesity, and others. The beginning and development of atherosclerosis has been associated with several immune components, including infiltration of inflammatory cells, monocyte/macrophage-derived foam cells, and inflammatory cytokines and chemokines. Mesenchymal stem cells (MSCs) originate from several tissue sources of the body and have self-renewal and multipotent differentiation characteristics. They also have immunomodulatory and anti-inflammatory properties. Recently, it was shown that MSCs have a regulatory role in plasma lipid levels. In addition, MSCs have shown to have promising potential in terms of treatment strategies for several diseases, including those with an inflammatory component. In this regard, transplantation of MSCs to patients with atherosclerosis has been proposed as a novel strategy in the treatment of this disease. In this review, we summarize the current advancements regarding MSCs for the treatment of atherosclerosis.
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Affiliation(s)
- Armita Mahdavi Gorabi
- Department of Basic and Clinical Research, Tehran Heart Center, Tehran University of Medical Sciences, Tehran 1411713138, Iran
| | - Maciej Banach
- Department of Hypertension, WAM University Hospital in Lodz, Medical University of Lodz, Zeromskiego 113, 90-549 Lodz, Poland
- Polish Mother's Memorial Hospital Research Institute (PMMHRI), 93-338 Lodz, Poland
| | - Željko Reiner
- Department of Internal medicine, University Hospital Center Zagreb, Kišpatićeva 12, Zagreb 1000, Croatia
| | - Matteo Pirro
- Unit of Internal Medicine, Angiology and Arteriosclerosis Diseases, Department of Medicine, University of Perugia, 06123 Perugia, Italy
| | - Saeideh Hajighasemi
- Department of Medical Biotechnology, Faculty of Paramedicine, Qazvin University of Medical Sciences, Qazvin 1531534199, Iran
| | - Thomas P Johnston
- Division of Pharmacology and Pharmaceutical Sciences, School of Pharmacy, University of Missouri-Kansas City, Kansas City, MO 64110, USA
| | - Amirhossein Sahebkar
- Biotechnology Research Center, Pharmaceutical Technology Institute, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
- Neurogenic Inflammation Research Center, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
- School of Pharmacy, Mashhad University of Medical Sciences, Mashhad 91778-99191, Iran.
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36
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Javan MR, Khosrojerdi A, Moazzeni SM. New Insights Into Implementation of Mesenchymal Stem Cells in Cancer Therapy: Prospects for Anti-angiogenesis Treatment. Front Oncol 2019; 9:840. [PMID: 31555593 PMCID: PMC6722482 DOI: 10.3389/fonc.2019.00840] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2019] [Accepted: 08/15/2019] [Indexed: 12/12/2022] Open
Abstract
Tumor microenvironment interacts with tumor cells, establishing an atmosphere to contribute or suppress the tumor development. Among the cells which play a role in the tumor microenvironment, mesenchymal stem cells (MSCs) have been demonstrated to possess the ability to orchestrate the fate of tumor cells, drawing the attention to the field. MSCs have been considered as cells with double-bladed effects, implicating either tumorigenic or anti-tumor activity. On the other side, the promising potential of MSCs in treating human cancer cells has been observed from the clinical studies. Among the beneficial characteristics of MSCs is the natural tumor-trophic migration ability, providing facility for drug delivery and, therefore, targeted treatment to detach tumor and metastatic cells. Moreover, these cells have been the target of engineering approaches, due to their easily implemented traits, in order to obtain the desired expression of anti-angiogenic, anti-proliferative, and pro-apoptotic properties, according to the tumor type. Tumor angiogenesis is the key characteristic of tumor progression and metastasis. Manipulation of angiogenesis has become an attractive approach for cancer therapy since the introduction of the first angiogenesis inhibitor, namely bevacizumab, for metastatic colorectal cancer therapy. This review tries to conclude the approaches, with focus on anti-angiogenesis approach, in implementing the MSCs to combat against tumor cell progression.
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Affiliation(s)
- Mohammad Reza Javan
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Arezou Khosrojerdi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
| | - Seyed Mohammad Moazzeni
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran
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Kamel M, Pavulraj S, Osterrieder K, Azab W. EHV-1 Pathogenesis: Current in vitro Models and Future Perspectives. Front Vet Sci 2019; 6:251. [PMID: 31417917 PMCID: PMC6684782 DOI: 10.3389/fvets.2019.00251] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2019] [Accepted: 07/12/2019] [Indexed: 01/09/2023] Open
Abstract
Primary infection and pathogenesis of equine herpesvirus type 1 (EHV-1) require an intricate interaction of virus with the mucosal epithelium, mononuclear cells and the vascular endothelium. Studies on EHV-1 have been facilitated by the development of different in vitro models that recapitulate the in vivo tissue complexity. The available in vitro assays can be categorized into (i) models mimicking the epithelium-peripheral blood mononuclear cell (PBMC) interaction, which include ex vivo mucosal (nasal and vaginal) explants and equine respiratory epithelial cells (EREC) cultures; and (ii) PBMC-endothelium mimicking models, including flow chamber and contact assays. These in vitro models have proven their worth in attempts to recapitulate the in vivo architecture and complexity, produce data relevant to natural host infection, and reduce animal use due to in vivo experiments. Although horse models are still needed for certain experiments, e.g., EHV-1 myeloencephalopathy or vaccination studies, available in vitro models can be used to obtain highly valuable data on virus-host tissue interactions. Microfluidic based 3D culture system (e.g., horse-on-a-chip) could be a potential upgraded version of these in vitro models for future research.
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Affiliation(s)
- Mohamed Kamel
- Institut für Virologie, Zentrum für Infektionsmedizin, Freie Universität Berlin, Berlin, Germany.,Department of Medicine and Infectious Diseases, Faculty of Veterinary Medicine, Cairo University, Giza, Egypt
| | - Selvaraj Pavulraj
- Institut für Virologie, Zentrum für Infektionsmedizin, Freie Universität Berlin, Berlin, Germany
| | - Klaus Osterrieder
- Institut für Virologie, Zentrum für Infektionsmedizin, Freie Universität Berlin, Berlin, Germany
| | - Walid Azab
- Institut für Virologie, Zentrum für Infektionsmedizin, Freie Universität Berlin, Berlin, Germany
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Jamalpoor Z, Taromi N, Soleimani M, Koudehi MF, Asgari A. In vitro interaction of human Wharton's jelly mesenchymal stem cells with biomimetic 3D scaffold. J Biomed Mater Res A 2019; 107:1166-1175. [DOI: 10.1002/jbm.a.36608] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2018] [Revised: 12/24/2018] [Accepted: 01/03/2019] [Indexed: 12/11/2022]
Affiliation(s)
- Zahra Jamalpoor
- Trauma Research CenterAja University of Medical Sciences Tehran Iran
| | - Nafise Taromi
- Department of Medical Biotechnology, Faculty of Allied MedicineIran University of Medical Sciences Tehran Iran
- Cellular and Molecular Research CenterIran University of Medical Sciences Tehran Iran
| | - Mansooreh Soleimani
- Cellular and Molecular Research CenterIran University of Medical Sciences Tehran Iran
- Department of AnatomyIran University of Medical Sciences Tehran Iran
| | | | - Alireza Asgari
- Aerospace Medicine Research CenterAja University of Medical Sciences Tehran Iran
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Evaluation of alginate hydrogel encapsulated mesenchymal stem cell migration in horses. Res Vet Sci 2019; 124:38-45. [PMID: 30826587 DOI: 10.1016/j.rvsc.2019.02.005] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2018] [Revised: 02/15/2019] [Accepted: 02/24/2019] [Indexed: 02/07/2023]
Abstract
Osteoarthritis is an incapacitating disease characterized by pain and a progressive decrease in joint mobility. The implantation of mesenchymal stem cells (MSCs) has shown promising results for its treatment. The challenge remains to keep the cells longer at the site of action, increasing their therapeutic potential. The aim of this study was to evaluate the effectiveness of the Qtracker® 655 nanocrystal marking on allogeneic synovial membrane (SM) MSCs, encapsulated in alginate hydrogel, evaluating the migration of these cells. The 10 radiocarpal joints were submitted to arthroscopic surgery (D0), divided into two groups. The chondral defect was treated according to the group: GA free-labelled MSCSM and GB labelled MSCSM microcapsules. Seven days after lesion induction and implantation of labelled cells, biopsies of the lesion site were performed in two animals, and fragments of SM and joint capsule also collected, which were frozen and later processed for fluorescence microscopy. The synovial fluid of the three animals was analyzed by flow cytometry three times - 3, 7 and 21 days after application. The cellular marking with the nanocrystals allowed the visualization of the cells in cartilage, synovial membrane, synovial fluid and articular capsule, but with a predilection for the synovial membrane and the lesion site was scarce. The labelled MSCSM in microcapsules were scarce in the synovial fluid and could be related to the small quantity of MSCs leaving the pores of the microcapsules, also favorable results, as the cells release paracrine effects acting for a long period until the cellular differentiation.
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40
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α2-HS Glycoprotein in Plasma Extracellular Vesicles Inhibits the Osteogenic Differentiation of Human Mesenchymal Stromal Cells In Vitro. Stem Cells Int 2019; 2019:7246479. [PMID: 30881463 PMCID: PMC6383392 DOI: 10.1155/2019/7246479] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2018] [Revised: 08/16/2018] [Accepted: 10/28/2018] [Indexed: 11/18/2022] Open
Abstract
Extracellular vesicles (Evs) contain diverse functional proteins, mRNAs, miRNAs, and DNA fragments, are secreted by various types of cells, and play important roles in cellular communication. Here, we show for the first time that plasma Evs inhibited the osteogenic differentiation of mesenchymal stromal cells (MSCs) in vitro and the level of inhibition was positively correlated with the plasma Evs concentration. Plasma Evs downregulated the expression of markers such as osteocalcin (OCN), Runt-related transcription factor 2 (Runx2), and Osterix at mRNA levels required for osteogenic differentiation and reduced pSmad1/5/8 levels in MSCs. Furthermore, pSmad1/5/8 levels increased and MSCs underwent normal osteogenic differentiation after Evs-derived α2-HS glycoprotein (AHSG) function was inhibited with an anti-AHSG neutralizing antibody. However, the levels of pERK1/2, active β-catenin, and HES1 were not significantly altered. Therefore, we propose that as essential components of the extracellular microenvironment of MSCs, plasma Evs are taken up by MSCs and subsequently repress osteogenic differentiation through an AHSG-mediated decrease in pSmad1/5/8 levels. Our work identifies plasma Evs as novel regulators of MSC osteogenic differentiation.
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41
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Gugjoo MB, Amarpal, Makhdoomi DM, Sharma GT. Equine Mesenchymal Stem Cells: Properties, Sources, Characterization, and Potential Therapeutic Applications. J Equine Vet Sci 2018; 72:16-27. [PMID: 30929778 DOI: 10.1016/j.jevs.2018.10.007] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2018] [Revised: 09/06/2018] [Accepted: 10/05/2018] [Indexed: 02/07/2023]
Abstract
Properties like sustained multiplication and self-renewal, and homing and multilineage differentiation to undertake repair of the damaged tissues make stem cells the lifeline for any living system. Therefore, stem cell therapy is regarded to carry immense therapeutic potential. Though the dearth of understanding about the basic biological properties and pathways involved in therapeutic benefits currently limit the application of stem cells in humans as well as animals, there are innumerable reports that suggest clinical benefits of stem cell therapy in equine. Among various stem cell sources, currently adult mesenchymal stem cells (MSCs) are preferred for therapeutic application in horse owing to their easy availability, capacity to modulate inflammation, and promote healing. Also the cells carry very limited teratogenic risk compared to the pluripotent stem cells. Mesenchymal stem cells were earlier considered mainly for musculoskeletal tissues, but now may also be utilized in other diverse clinical problems in horse, and the results may be extrapolated even for human medicine. The current review highlights biological properties, sources, mechanisms, and potential therapeutic applications of stem cells in equine practice.
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Affiliation(s)
- Mudasir Bashir Gugjoo
- Division of Surgery, Indian Veterinary Research Institute-Izatnagar, Bareilly, UP, India.
| | - Amarpal
- Division of Surgery, Indian Veterinary Research Institute-Izatnagar, Bareilly, UP, India
| | - Dil Mohammad Makhdoomi
- Division of Surgery, Faculty of Veterinary Sciences and Animal Husbandry, Shuhama, SKUAST-Kashmir, Srinagar, J&K, India
| | - Gutulla Taru Sharma
- Division of Physiology and Climatology, Indian Veterinary Research Institute-Izatnagar, Bareilly, UP, India
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Kim HK, Lee SG, Lee SW, Oh BJ, Kim JH, Kim JA, Lee G, Jang JD, Joe YA. A Subset of Paracrine Factors as Efficient Biomarkers for Predicting Vascular Regenerative Efficacy of Mesenchymal Stromal/Stem Cells. Stem Cells 2018; 37:77-88. [PMID: 30281870 DOI: 10.1002/stem.2920] [Citation(s) in RCA: 53] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2018] [Revised: 08/22/2018] [Accepted: 08/28/2018] [Indexed: 12/27/2022]
Abstract
Mesenchymal stromal/stem cells (MSCs) have been developed as a promising source for cell-based therapies of ischemic disease. However, there are some hurdles in their clinical application such as poor cell engraftment and inconsistent stem cell potency. In this study, we sought to find biomarkers for predicting potency of MSCs for proangiogenic therapy to improve their beneficial effects. Large variations were observed in proangiogenic factor secretion profiles of conditioned media derived from nine different donor-derived Wharton's jelly (WJ)-derived MSCs and 8 factors among 55 angiogenesis-related factors were secreted at considerable levels. Two distinct WJ-MSCs that had the lowest or the highest secretion of these eight factors showed corresponding proangiogenic activities in in vitro angiogenesis assays. When four additional different donor-derived WJ-MSCs were further examined, proangiogenic activities in migration and tube formation of endothelial cells and in in vivo Matrigel plug assay were highly consistent with secretion levels of four major factors (angiogenin, interleukin-8, monocyte chemoattractant protein-1, and vascular endothelial growth factor). Such correlation was also observed in vascular regenerative effect in a mouse hind limb ischemia model. Blocking of these four factors by neutralizing antibodies or knockdown of them by siRNA treatment resulted in significant inhibition of proangiogenic activities of not only WJ-MSCs, but also bone marrow-derived MSCs. These results suggest that these four factors may represent efficient biomarkers for predicting vascular regenerative efficacy of MSCs. Stem Cells 2019;37:77-88.
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Affiliation(s)
- Hyun-Kyung Kim
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seul-Gi Lee
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea
| | - Seung-Woo Lee
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Bae Jun Oh
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea.,New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation (DGMIF), Daegu, Republic of Korea
| | - Jae Hyeon Kim
- Division of Endocrinology and Metabolism, Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Republic of Korea
| | - Jeong A Kim
- Division of Hematology, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Guisera Lee
- Department of Obstetrics and Gynecology, St. Vincent Hospital of Catholic University of Korea, Suwon, Republic of Korea
| | - Jae-Deog Jang
- Catholic Institute of Cell Therapy, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Young Ae Joe
- Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Medical Lifescience, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Cancer Evolution Research Center, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea.,Department of Biomedicine & Health Sciences, The Catholic University of Korea, Seoul, Republic of Korea
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Innate immune responses of equine monocytes cultured in equine platelet lysate. Vet Immunol Immunopathol 2017; 195:65-71. [PMID: 29249319 DOI: 10.1016/j.vetimm.2017.11.005] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Revised: 11/12/2017] [Accepted: 11/15/2017] [Indexed: 12/12/2022]
Abstract
Platelet lysate (PL) has been extensively used for the laboratory expansion of human mesenchymal stem cells (MSC) in order to avoid fetal bovine serum (FBS) which has been associated with immune-mediated host reactions and transmission of bovine-origin microbial contaminants. Before suggesting the routine use of PL for MSC culture, we wanted to further investigate whether PL alone might trigger inflammatory responses when exposed to reactive white blood cells such as monocytes. Our objectives were to evaluate the inflammatory profile of equine monocytes cultured with equine PL (ePL) and to determine if ePL can modulate the expression of inflammatory cytokines in lipopolysaccharide (LPS)-stimulated monocytes. In a first experiment, equine monocytes were isolated and incubated with donor horse serum (DHS), FBS, six individual donors ePL or pooled ePL from all horses. In a second experiment, monocytes were stimulated with E. coli LPS in the presence of 1, 5 or 10% DHS and/or pooled ePL. After 6h of incubation, cell culture supernatants were assayed via ELISA for production of the pro-inflammatory cytokines tumor necrosis factor alpha (TNF-α) and Interleukin 1β (IL-1β) as well as for the anti-inflammatory Interleukin 10 (IL-10). Equine monocytes incubated with pooled ePL produced significantly less TNF-α and significantly more IL-10 than monocytes incubated in FBS. A statistically significant difference was not identified for the production of IL-1β. The second experiment showed that pooled ePL added to LPS-stimulated equine monocytes resulted in a significant reduction in TNF-α and IL-1β production. IL-10 production was not significantly upregulated by the addition of ePL to LPS-stimulated monocytes. Finally, the addition of ePL to LPS-stimulated monocytes in the presence of various concentrations of DHS resulted to statistically significant decrease of TNF-α and IL-1β compared to the control groups. This is the first study to demonstrate that ePL suppresses the release of pro-inflammatory cytokines from stimulated equine monocytes. These results encourage further exploration of PL as a homologous media substitute for FBS but also opens the possibility of investigating its use as means to suppress cell-mediated inflammation.
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Bearden RN, Huggins SS, Cummings KJ, Smith R, Gregory CA, Saunders WB. In-vitro characterization of canine multipotent stromal cells isolated from synovium, bone marrow, and adipose tissue: a donor-matched comparative study. Stem Cell Res Ther 2017; 8:218. [PMID: 28974260 PMCID: PMC5627404 DOI: 10.1186/s13287-017-0639-6] [Citation(s) in RCA: 55] [Impact Index Per Article: 6.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2016] [Revised: 07/06/2017] [Accepted: 07/24/2017] [Indexed: 12/14/2022] Open
Abstract
Background The dog represents an excellent large animal model for translational cell-based studies. Importantly, the properties of canine multipotent stromal cells (cMSCs) and the ideal tissue source for specific translational studies have yet to be established. The aim of this study was to characterize cMSCs derived from synovium, bone marrow, and adipose tissue using a donor-matched study design and a comprehensive series of in-vitro characterization, differentiation, and immunomodulation assays. Methods Canine MSCs were isolated from five dogs with cranial cruciate ligament rupture. All 15 cMSC preparations were evaluated using colony forming unit (CFU) assays, flow cytometry analysis, RT-PCR for pluripotency-associated genes, proliferation assays, trilineage differentiation assays, and immunomodulation assays. Data were reported as mean ± standard deviation and compared using repeated-measures analysis of variance and Tukey post-hoc test. Significance was established at p < 0.05. Results All tissue samples produced plastic adherent, spindle-shaped preparations of cMSCs. Cells were negative for CD34, CD45, and STRO-1 and positive for CD9, CD44, and CD90, whereas the degree to which cells were positive for CD105 was variable depending on tissue of origin. Cells were positive for the pluripotency-associated genes NANOG, OCT4, and SOX2. Accounting for donor and tissue sources, there were significant differences in CFU potential, rate of proliferation, trilineage differentiation, and immunomodulatory response. Synovium and marrow cMSCs exhibited superior early osteogenic activity, but when assessing late-stage osteogenesis no significant differences were detected. Interestingly, bone morphogenic protein-2 (BMP-2) supplementation was necessary for early-stage and late-stage osteogenic differentiation, a finding consistent with other canine studies. Additionally, synovium and adipose cMSCs proliferated more rapidly, displayed higher CFU potential, and formed larger aggregates in chondrogenic assays, although proteoglycan and collagen type II staining were subjectively decreased in adipose pellets as compared to synovial and marrow pellets. Lastly, cMSCs derived from all three tissue sources modulated murine macrophage TNF-α and IL-6 levels in a lipopolysaccharide-stimulated coculture assay. Conclusions While cMSCs from synovium, marrow, and adipose tissue share a number of similarities, important differences in proliferation and trilineage differentiation exist and should be considered when selecting cMSCs for translational studies. These results and associated methods will prove useful for future translational studies involving the canine model. Electronic supplementary material The online version of this article (doi:10.1186/s13287-017-0639-6) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Robert N Bearden
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Shannon S Huggins
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Kevin J Cummings
- Department of Veterinary Integrative Biosciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Roger Smith
- Department of Veterinary Pathobiology, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA
| | - Carl A Gregory
- Department of Molecular and Cellular Medicine, Institute for Regenerative Medicine, College of Medicine, Texas A&M University, College Station, TX, USA
| | - William B Saunders
- Department of Small Animal Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Texas A&M University, College Station, TX, USA.
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Parameswaran S, Krishnakumar S. Pluripotent stem cells: A therapeutic source for age-related macular degeneration. Indian J Ophthalmol 2017; 65:177-183. [PMID: 28440245 PMCID: PMC5426121 DOI: 10.4103/ijo.ijo_1026_15] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Age-related macular degeneration (AMD) leads to progressive loss of central vision in the elderly. At a cellular level, there is aging of the retinal pigment epithelial (RPE) cells, and accumulation of lipofuscin that interferes with the proper functioning of RPE which eventually leads to apoptosis. Treatment depends on the stage of the disease. Wet AMD which has neovascularization is managed by local therapies such as laser photocoagulation and photodynamic therapy and is managed with injections of antivascular endothelial growth factor-based therapy. Unlike the wet AMD, an effective therapy does not exist for dry AMD and geographic atrophy. Cell replacement therapy has shown promise. This review discusses the opportunities in the various types of cell-based therapy, their limitations, and what is possible for India.
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Affiliation(s)
- Sowmya Parameswaran
- L and T Ophthalmic Pathology, Radheshyam Kanoi Stem Cell Laboratory, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
| | - Subramanian Krishnakumar
- L and T Ophthalmic Pathology, Radheshyam Kanoi Stem Cell Laboratory, Vision Research Foundation, Sankara Nethralaya, Chennai, Tamil Nadu, India
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TNF- α Induced the Enhanced Apoptosis of Mesenchymal Stem Cells in Ankylosing Spondylitis by Overexpressing TRAIL-R2. Stem Cells Int 2017; 2017:4521324. [PMID: 28182106 PMCID: PMC5274669 DOI: 10.1155/2017/4521324] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2016] [Accepted: 12/04/2016] [Indexed: 12/11/2022] Open
Abstract
Ankylosing spondylitis (AS) is an autoimmune disease with unknown etiology. Dysregulated mesenchymal stem cells (MSCs) apoptosis may contribute to the pathogenesis of autoimmune diseases. However, apoptosis of MSCs from patients with AS (ASMSCs) has not been investigated yet. The present study aims to assess the apoptosis of bone marrow-derived ASMSCs and to investigate the underlying mechanisms of altered ASMSCs apoptosis. We successfully induced the apoptosis of ASMSCs and MSCs from healthy donors (HDMSCs) using the combination of tumor necrosis factor alpha (TNF-α) and cycloheximide (CHX). We found that ASMSCs treated with TNF-α and CHX showed higher apoptosis levels compared to HDMSCs. During apoptosis, ASMSCs expressed significantly more TRAIL-R2, which activated both the death receptor pathway and mitochondria pathway by increasing the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3. Inhibiting TRAIL-R2 expression using shRNA eliminated the apoptosis differences between HDMSCs and ASMSCs by partially reducing ASMSCs apoptosis but minimally affecting that of HDMSCs. Furthermore, the expression of FADD, cleaved caspase-8, cytosolic cytochrome C, and cleaved caspase-3 were comparable between HDMSCs and ASMSCs after TRAIL-R2 inhibition. These results indicated that increased TRAIL-R2 expression results in enhanced ASMSCs apoptosis and may contribute to AS pathogenesis.
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Characterization and Expression of Senescence Marker in Prolonged Passages of Rat Bone Marrow-Derived Mesenchymal Stem Cells. Stem Cells Int 2016; 2016:8487264. [PMID: 27579045 PMCID: PMC4989133 DOI: 10.1155/2016/8487264] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 05/23/2016] [Accepted: 05/23/2016] [Indexed: 12/15/2022] Open
Abstract
The present study is aimed at optimizing the in vitro culture protocol for generation of rat bone marrow- (BM-) derived mesenchymal stem cells (MSCs) and characterizing the culture-mediated cellular senescence. The initial phase of generation and characterization was conducted using the adherent cells from Sprague Dawley (SD) rat's BM via morphological analysis, growth kinetics, colony forming unit capacity, immunophenotyping, and mesodermal lineage differentiation. Mesenchymal stem cells were successfully generated and characterized as delineated by the expressions of CD90.1, CD44H, CD29, and CD71 and lack of CD11b/c and CD45 markers. Upon induction, rBM-MSCs differentiated into osteocytes and adipocytes and expressed osteocytes and adipocytes genes. However, a decline in cell growth was observed at passage 4 onwards and it was further deciphered through apoptosis, cell cycle, and senescence assays. Despite the enhanced cell viability at later passages (P4-5), the expression of senescence marker, β-galactosidase, was significantly increased at passage 5. Furthermore, the cell cycle analysis has confirmed the in vitro culture-mediated cellular senescence where cells were arrested at the G0/G1 phase of cell cycle. Although the currently optimized protocols had successfully yielded rBM-MSCs, the culture-mediated cellular senescence limits the growth of rBM-MSCs and its potential use in rat-based MSC research.
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Xie Z, Wang P, Li Y, Deng W, Zhang X, Su H, Li D, Wu Y, Shen H. Imbalance Between Bone Morphogenetic Protein 2 and Noggin Induces Abnormal Osteogenic Differentiation of Mesenchymal Stem Cells in Ankylosing Spondylitis. Arthritis Rheumatol 2016; 68:430-40. [PMID: 26413886 DOI: 10.1002/art.39433] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Accepted: 09/08/2015] [Indexed: 12/14/2022]
Abstract
OBJECTIVE To study the osteogenic differentiation capacity of bone marrow-derived mesenchymal stem cells (BM-MSCs) from patients with ankylosing spondylitis (AS) and to investigate the mechanisms of abnormal osteogenic differentiation of BM-MSCs in AS. METHODS BM-MSCs from healthy donors (HD-MSCs) and patients with AS (AS-MSCs) were cultured in osteogenic differentiation medium for 0-21 days, after which their osteogenic differentiation capacity was determined using alizarin red S and alkaline phosphatase assays. Gene expression levels of osteoblastic markers and related cytokines were detected by high-throughput quantitative reverse transcription-polymerase chain reaction. Enzyme-linked immunosorbent assay was performed to detect protein levels of bone morphogenetic protein 2 (BMP-2) and Noggin in the cell culture supernatant. The activation of Smad1/5/8 and MAPK signaling pathways was measured by Western blotting. The balance between BMP-2 and Noggin expression was regulated using lentiviruses encoding short hairpin RNA and exogenous Noggin, respectively, which enabled evaluation of how this balance affected osteogenic differentiation of AS-MSCs. RESULTS AS-MSCs outperformed HD-MSCs in osteogenic differentiation capacity. During osteogenic differentiation, AS-MSCs secreted more BMP-2 but less Noggin, accompanied by an overactivation of Smad1/5/8 and ERK-1/2. When the Noggin concentration was increased or BMP-2 expression was inhibited, the abnormal osteogenic differentiation of AS-MSCs was rectified. In addition, the balance between BMP-2 and Noggin secretion was restored. CONCLUSION The results of this study demonstrate that an imbalance between BMP-2 and Noggin secretion induces abnormal osteogenic differentiation of AS-MSCs. These findings reveal a mechanism of pathologic osteogenesis in AS and provide a new perspective on inhibiting pathologic osteogenesis by regulating the balance between BMP-2 and Noggin.
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Affiliation(s)
- Zhongyu Xie
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Peng Wang
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Yuxi Li
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Wen Deng
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Xin Zhang
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Hongjun Su
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Deng Li
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Yanfeng Wu
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
| | - Huiyong Shen
- Sun Yat-sen Memorial Hospital and Sun Yat-sen University, Guangzhou, China
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Espinosa P, Spriet M, Sole A, Walker NJ, Vaughan B, Galuppo LD. Scintigraphic Tracking of Allogeneic Mesenchymal Stem Cells in the Distal Limb After Intra-Arterial Injection in Standing Horses. Vet Surg 2016; 45:619-24. [DOI: 10.1111/vsu.12485] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2015] [Accepted: 02/16/2016] [Indexed: 12/01/2022]
Affiliation(s)
- Pablo Espinosa
- Veterinary Medical Teaching Hospital, School of Veterinary Medicine; University of California; Davis Davis, California
| | - Mathieu Spriet
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine; University of California; Davis Davis, California
| | - Albert Sole
- Veterinary Medical Teaching Hospital, School of Veterinary Medicine; University of California; Davis Davis, California
| | - Naomi J. Walker
- Department of Pathology, Microbiology and Immunology, School of Veterinary Medicine; University of California; Davis Davis, California
| | - Betsy Vaughan
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine; University of California; Davis Davis, California
| | - Larry D. Galuppo
- Department of Surgical and Radiological Sciences, School of Veterinary Medicine; University of California; Davis Davis, California
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Immortalisation with hTERT Impacts on Sulphated Glycosaminoglycan Secretion and Immunophenotype in a Variable and Cell Specific Manner. PLoS One 2015. [PMID: 26196672 PMCID: PMC4510558 DOI: 10.1371/journal.pone.0133745] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Background Limited options for the treatment of cartilage damage have driven the development of tissue engineered or cell therapy alternatives reliant on ex vivo cell expansion. The study of chondrogenesis in primary cells is difficult due to progressive cellular aging and senescence. Immortalisation via the reintroduction of the catalytic component of telomerase, hTERT, could allow repeated, longitudinal studies to be performed while bypassing senescent phenotypes. Methods Three human cell types: bone marrow-derived stromal cells (BMA13), embryonic stem cell-derived (1C6) and chondrocytes (OK3) were transduced with hTERT (BMA13H, 1C6H and OK3H) and proliferation, surface marker expression and tri-lineage differentiation capacity determined. The sulphated glycosaminoglycan (sGAG) content of the monolayer and spent media was quantified in maintenance media (MM) and pro-chondrogenic media (PChM) and normalised to DNA. Results hTERT expression was confirmed in transduced cells with proliferation enhancement in 1C6H and OK3H cells but not BMA13H. All cells were negative for leukocyte markers (CD19, CD34, CD45) and CD73 positive. CD14 was expressed at low levels on OK3 and OK3H and HLA-DR on BMA13 (84.8%). CD90 was high for BMA13 (84.9%) and OK3 (97.3%) and moderate for 1C6 (56.7%), expression was reduced in BMA13H (33.7%) and 1C6H (1.6%). CD105 levels varied (BMA13 87.7%, 1C6 8.2%, OK3 43.3%) and underwent reduction in OK3H (25.1%). 1C6 and BMA13 demonstrated osteogenic and adipogenic differentiation but mineralised matrix and lipid accumulation appeared reduced post hTERT transduction. Chondrogenic differentiation resulted in increased monolayer-associated sGAG in all primary cells and 1C6H (p<0.001), and BMA13H (p<0.05). In contrast OK3H demonstrated reduced monolayer-associated sGAG in PChM (p<0.001). Media-associated sGAG accounted for ≥55% (PChM-1C6) and ≥74% (MM-1C6H). Conclusion In conclusion, hTERT transduction could, but did not always, prevent senescence and cell phenotype, including differentiation potential, was affected in a variable manner. As such, these cells are not a direct substitute for primary cells in cartilage regeneration research.
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