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Innis A, Bousso I, Roberts DA, Marshall BP, Song L, Thomopoulos S. Adipose derived stem cell activation by macrophages and tendon fibroblasts. Regen Med 2025:1-11. [PMID: 40415332 DOI: 10.1080/17460751.2025.2510098] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2025] [Accepted: 05/20/2025] [Indexed: 05/27/2025] Open
Abstract
AIMS Tendon injuries are common, and healing often fails due to an over-exuberant inflammatory response and a lack of regeneration. Inflammatory cells play key roles in these processes, with a balance between classically activated pro-inflammatory M1 macrophages and alternatively activated inflammatory resolving M2 macrophages. Adipose-derived mesenchymal stem cells (ASCs) can dampen the pro-inflammatory effectsof macrophages, promote a regenerative environment, and enhance healing. Therefore, the goal of the study was to understand how ASCs are activated by macrophages in vitro. METHODS In vitro co-culture experiments were carried out with ASCs, macrophages, and tendon fibroblasts. RNA-seq and qRT-PCR were performed to determine expression patterns of activated ASCs. RESULTS M1 macrophages prompted ASCs to upregulate pro-inflammatory signaling, matrix remodeling, and cytokine production pathways, while downregulating those related to cell adhesion and cell cycle. Conversely, TFs prompted ASCs to upregulate pathways involved in cell cycle and cytoskeleton remodeling, and to downregulate pathways associated with immune cell adhesion, inflammatory mediator production, and protein metabolism. CONCLUSIONS The cell-specific activation profiles indicate a possible switch in ASC paracrine signaling depending on the context, from a pro-inflammatory pattern in response to M1 macrophages to a proliferative pattern in response to TFs. Understanding crosstalk between ASCs, TFs, and macrophages is essential for developing stem cell-based therapeutic strategies.
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Affiliation(s)
- Astia Innis
- Department of Orthopedic Surgery, Columbia University, New York, NY, USA
- School of Medicine, Tufts University, Boston, MA, USA
| | - Ismael Bousso
- Department of Orthopedic Surgery, Columbia University, New York, NY, USA
| | - David Aaron Roberts
- Department of Orthopedic Surgery, Columbia University, New York, NY, USA
- College of Osteopathic Medicine, Touro University, New York, NY, USA
| | | | - Lee Song
- Department of Orthopedic Surgery, Columbia University, New York, NY, USA
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Ning J, Sah RK, Wang J. Coculture of mesenchymal stem cells and macrophage: A narrative review. J Pharmacol Exp Ther 2025; 392:103531. [PMID: 40154096 DOI: 10.1016/j.jpet.2025.103531] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2024] [Accepted: 02/24/2025] [Indexed: 04/01/2025] Open
Abstract
Stem cell transplantation is a promising treatment for repairing damaged tissues, but challenges like immune rejection and ethical concerns remain. Mesenchymal stem cells (MSCs) offer high differentiation potential and immune regulatory activity, showing promise in treating diseases such as gynecological, neurological, and kidney disorders. With scientific progress, MSC applications are overcoming traditional treatment limitations. In MSCs-macrophage coculture, MSCs transform macrophages into anti-inflammatory M2 macrophages, reducing inflammation, whereas macrophages enhance MSCs osteogenic differentiation. This coculture is vital for immune modulation and tissue repair, with models varying by contact type and dimensional arrangements. Factors such as coculture techniques and cell ratios influence outcomes. Benefits include improved heart function, wound healing, reduced lung inflammation, and accelerated bone repair. Challenges include optimizing coculture conditions. This study reviews the methodologies, factors, and mechanisms of MSC-macrophage coculture, providing a foundation for tissue engineering applications. SIGNIFICANCE STATEMENT: This review underlines the significant role of mesenchymal stem cell-macrophage coculture, providing a foundation for tissue engineering application.
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Affiliation(s)
- Jun Ning
- Department of General Gynecology II, Gynecology and Obstetrics Center, the First Hospital of Jilin University, Changchun, China
| | - Rajiv Kumar Sah
- Department of Pediatrics, Hematology/Oncology, Baylor College of Medicine, Houston, Texas; Texas Children's Hospital, Houston, Texas
| | - Jing Wang
- Department of Reproductive Medicine, Department of Prenatal Diagnosis, The First Hospital of Jilin University, Changchun, China.
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3
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Liu C, Guo J, Guan L, Li J, Xu B, Zhao H. Protective effects of melatonin on stroke in diabetic mice: central and peripheral inflammation modulation. Stroke Vasc Neurol 2025:svn-2024-003442. [PMID: 40000029 DOI: 10.1136/svn-2024-003442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2024] [Accepted: 01/17/2025] [Indexed: 02/27/2025] Open
Abstract
BACKGROUND Melatonin protects against ischaemic stroke in diabetic animal models, though the mechanisms involving brain and peripheral immune responses remain underexplored. We aimed to clarify how melatonin interacts with these immune responses to protect against stroke in diabetic mice. METHODS Type 1 diabetes mellitus (T1DM) was induced in mice using streptozotocin. RNA sequencing of brain tissue and peripheral blood mononuclear cells (PBMCs) was performed 24 hours poststroke. Inflammatory responses were evaluated 72 hours after ischaemia/reperfusion. RESULTS Melatonin reduced infarction and improved neurological function in T1DM mice. In the ischaemic brain, melatonin downregulated inflammatory factor expression, with bioinformatics identifying 62 differentially expressed genes (DEGs) related to inflammation and 11 associated with inflammasomes. Western blotting confirmed reductions in NLRP3, HMGB1 and Cleaved Caspase-1 expression. Flow cytometry showed reduced infiltration of CD8+T cells and neutrophils. Melatonin decreased IL-6, IL-1β and IL-4 levels. In PBMCs, RNA sequencing revealed 939 DEGs following melatonin treatment. Kyoto Encyclopaedia of Genes and Genomes analysis indicated that downregulated DEGs were involved in metabolic pathways, and upregulated DEGs were enriched in the Jak-STAT signalling pathway. GO analysis showed that downregulated DEGs were enriched in the cytosol, and upregulated DEGs related to macromolecule modification. Protein-protein interaction analysis revealed that melatonin affected 38 inflammation-associated genes linked to key cytokines (Il6, Il1b, Ifng, Il4). Flow cytometry indicated melatonin increased CD8+T cells, monocytes and neutrophils in the blood, suggesting a reversal of immunosuppression. Multiplex cytokine assays showed melatonin decreased IL-6 and IFN-γ levels. CONCLUSION Poststroke melatonin therapy reduces ischaemic brain damage in T1DM mice by modulating central and peripheral inflammatory responses.
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Affiliation(s)
- Cuiying Liu
- School of Nursing, Capital Medical University, Beijing, China
| | - Jiayi Guo
- Department of Neurobiology, School of Basic Medical Science, Capital Medical University, Beijing, China
| | - Longfei Guan
- China-America Institute of Neuroscience, Beijing Luhe Hospital, Capital Medical University, Beijing, China
| | - Junfa Li
- Department of Neurobiology, School of Basic Medical Science, Capital Medical University, Beijing, China
| | - Baohui Xu
- Division of Vascular Surgery, Department of Surgery, Stanford University School of Medicine, Stanford, California, USA
| | - Heng Zhao
- Beijing Institute of Brain Disorders, Laboratory of Brain Disorders, Ministry of Science and Technology, Collaborative Innovation Center for Brain Disorders, Capital Medical University, Beijing, China
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Yang Y, Wu A, Deng AN, Liu H, Lan Q, Mazhar M, Xue JY, Chen MT, Luo G, Liu MN. Macrophages after myocardial infarction: Mechanisms for repairing and potential as therapeutic approaches. Int Immunopharmacol 2024; 143:113562. [PMID: 39536484 DOI: 10.1016/j.intimp.2024.113562] [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: 09/21/2024] [Revised: 10/20/2024] [Accepted: 10/31/2024] [Indexed: 11/16/2024]
Abstract
Macrophages - one of the crucial immune cells, are recruited to the cardiac tissue by chemokines, cytokines and upregulated endothelial adhesion molecules after myocardial infarction (MI). During the course of inflammation in the cardiac tissue, necrotic cells and matrix debris is phagocytosed by M1 macrophages. During the resolution phase of cardiac inflammation, M2 macrophages promote cardiac recovery. Suppression or over expression of both the M1 and M2 macrophage subtypes significantly affect the reparation of infarction. Stem cells therapy, cytokine regulation and immune cells therapy are considered as effective interventions to regulate the phenotypic transformation of cardiac macrophages after MI. Intervention with macrophages in the myocardium has shown unique advantages. In this review, the mechanisms and role of macrophages in the development of MI are elaborated in detail, the promising therapeutic methods for regulating macrophage phenotypes, their limitations and possible future research directions are discussed.
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Affiliation(s)
- You Yang
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Ai Wu
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - An-Ni Deng
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Hao Liu
- Department of Pediatrics, The Affiliated Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Qi Lan
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Maryam Mazhar
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Jin-Yi Xue
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China
| | - Ming-Tai Chen
- Department of Cardiovascular Disease, Shenzhen Traditional Chinese Medicine Hospital, Shenzhen, Guangdong, China.
| | - Gang Luo
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
| | - Meng-Nan Liu
- Affiliated Traditional Chinese Medicine Hospital, Southwest Medical University, Luzhou, Sichuan, China.
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5
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Tang XL, Wysoczynski M, Gumpert AM, Solanki M, Li Y, Wu WJ, Zheng S, Ruble H, Li H, Stowers H, Zheng S, Ou Q, Tanveer N, Slezak J, Kalra DK, Bolli R. Intravenous infusions of mesenchymal stromal cells have cumulative beneficial effects in a porcine model of chronic ischaemic cardiomyopathy. Cardiovasc Res 2024; 120:1939-1952. [PMID: 39163570 PMCID: PMC11630033 DOI: 10.1093/cvr/cvae173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2024] [Revised: 07/08/2024] [Accepted: 07/23/2024] [Indexed: 08/22/2024] Open
Abstract
AIMS The development of cell therapy as a widely available clinical option for ischaemic cardiomyopathy is hindered by the invasive nature of current cell delivery methods. Furthermore, the rapid disappearance of cells after transplantation provides a cogent rationale for using repeated cell doses, which, however, has not been done thus far in clinical trials because it is not feasible with invasive approaches. The goal of this translational study was to test the therapeutic utility of the intravenous route for cell delivery. METHODS AND RESULTS Pigs with chronic ischaemic cardiomyopathy induced by myocardial infarction received one or three intravenous doses of allogeneic bone marrow mesenchymal stromal cells (MSCs) or placebo 35 days apart. Rigour guidelines, including blinding and randomization, were strictly followed. A comprehensive assessment of left ventricular (LV) function was conducted with three independent methods (echocardiography, magnetic resonance imaging, and haemodynamic studies). The results demonstrate that three doses of MSCs improved both load-dependent and independent indices of LV function and reduced myocardial hypertrophy and fibrosis; in contrast, one dose failed to produce most of these benefits. CONCLUSIONS To our knowledge, this is the first study to show that intravenous infusion of a cell product improves LV function and structure in a large animal model of chronic ischaemic cardiomyopathy and that repeated infusions are necessary to produce robust effects. This study, conducted in a clinically relevant model, supports a new therapeutic strategy based on repeated intravenous infusions of allogeneic MSCs and provides a foundation for a first-in-human trial testing this strategy in patients with chronic ischaemic cardiomyopathy.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Marcin Wysoczynski
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Anna M Gumpert
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Mitesh Solanki
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Yan Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Wen-Jian Wu
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Shirong Zheng
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Halina Ruble
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Hong Li
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Heather Stowers
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Shengnan Zheng
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Qinghui Ou
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Nida Tanveer
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Jan Slezak
- Centre of Experimental Medicine, Institute for Heart Research, Bratislava, Slovakia
| | - Dinesh K Kalra
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, 550 S Jackson Street, ACB Bldg, 3rd Floor, Louisville, KY 40202
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Yahyazadeh R, Baradaran Rahimi V, Askari VR. Stem cell and exosome therapies for regenerating damaged myocardium in heart failure. Life Sci 2024; 351:122858. [PMID: 38909681 DOI: 10.1016/j.lfs.2024.122858] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Finding novel treatments for cardiovascular diseases (CVDs) is a hot topic in medicine; cell-based therapies have reported promising news for controlling dangerous complications of heart disease such as myocardial infarction (MI) and heart failure (HF). Various progenitor/stem cells were tested in various in-vivo, in-vitro, and clinical studies for regeneration or repairing the injured tissue in the myocardial to accelerate the healing. Fetal, adult, embryonic, and induced pluripotent stem cells (iPSC) have revealed the proper potency for cardiac tissue repair. As an essential communicator among cells, exosomes with specific contacts (proteins, lncRNAs, and miRNAs) greatly promote cardiac rehabilitation. Interestingly, stem cell-derived exosomes have more efficiency than stem cell transplantation. Therefore, stem cells induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), cardiac stem cells (CDC), and skeletal myoblasts) and their-derived exosomes will probably be considered an alternative therapy for CVDs remedy. In addition, stem cell-derived exosomes have been used in the diagnosis/prognosis of heart diseases. In this review, we explained the advances of stem cells/exosome-based treatment, their beneficial effects, and underlying mechanisms, which will present new insights in the clinical field in the future.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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Hetta HF, Elsaghir A, Sijercic VC, Akhtar MS, Gad SA, Moses A, Zeleke MS, Alanazi FE, Ahmed AK, Ramadan YN. Mesenchymal stem cell therapy in diabetic foot ulcer: An updated comprehensive review. Health Sci Rep 2024; 7:e2036. [PMID: 38650719 PMCID: PMC11033295 DOI: 10.1002/hsr2.2036] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2023] [Revised: 02/06/2024] [Accepted: 03/19/2024] [Indexed: 04/25/2024] Open
Abstract
Background Diabetes has evolved into a worldwide public health issue. One of the most serious complications of diabetes is diabetic foot ulcer (DFU), which frequently creates a significant financial strain on patients and lowers their quality of life. Up until now, there has been no curative therapy for DFU, only symptomatic relief or an interruption in the disease's progression. Recent studies have focused attention on mesenchymal stem cells (MSCs), which provide innovative and potential treatment candidates for several illnesses as they can differentiate into various cell types. They are mostly extracted from the placenta, adipose tissue, umbilical cord (UC), and bone marrow (BM). Regardless of their origin, they show comparable features and small deviations. Our goal is to investigate MSCs' therapeutic effects, application obstacles, and patient benefit strategies for DFU therapy. Methodology A comprehensive search was conducted using specific keywords relating to DFU, MSCs, and connected topics in the databases of Medline, Scopus, Web of Science, and PubMed. The main focus of the selection criteria was on English-language literature that explored the relationship between DFU, MSCs, and related factors. Results and Discussion Numerous studies are being conducted and have demonstrated that MSCs can induce re-epithelialization and angiogenesis, decrease inflammation, contribute to immunological modulation, and subsequently promote DFU healing, making them a promising approach to treating DFU. This review article provides a general snapshot of DFU (including clinical presentation, risk factors and etiopathogenesis, and conventional treatment) and discusses the clinical progress of MSCs in the management of DFU, taking into consideration the side effects and challenges during the application of MSCs and how to overcome these challenges to achieve maximum benefits. Conclusion The incorporation of MSCs in the management of DFU highlights their potential as a feasible therapeutic strategy. Establishing a comprehensive understanding of the complex relationship between DFU pathophysiology, MSC therapies, and related obstacles is essential for optimizing therapy outcomes and maximizing patient benefits.
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Affiliation(s)
- Helal F. Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative MedicineFaculty of Pharmacy, University of TabukTabukSaudi Arabia
- Department of Medical Microbiology and ImmunologyFaculty of Medicine, Assiut UniversityAssiutEgypt
| | - Alaa Elsaghir
- Department of Microbiology and ImmunologyFaculty of Pharmacy, Assiut UniversityAssiutEgypt
| | | | | | - Sayed A. Gad
- Faculty of Medicine, Assiut UniversityAssiutEgypt
| | | | - Mahlet S. Zeleke
- Menelik II Medical and Health Science College, Kotebe Metropolitan UniversityAddis AbabaEthiopia
| | - Fawaz E. Alanazi
- Department of Pharmacology and ToxicologyFaculty of Pharmacy, University of TabukTabukSaudi Arabia
| | | | - Yasmin N. Ramadan
- Department of Microbiology and ImmunologyFaculty of Pharmacy, Assiut UniversityAssiutEgypt
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Pilny E, Czapla J, Drzyzga A, Smolarczyk R, Matuszczak S, Jarosz-Biej M, Krakowczyk Ł, Cichoń T. The comparison of adipose-derived stromal cells (ADSCs) delivery method in a murine model of hindlimb ischemia. Stem Cell Res Ther 2024; 15:27. [PMID: 38303049 PMCID: PMC10836003 DOI: 10.1186/s13287-024-03634-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2022] [Accepted: 01/08/2024] [Indexed: 02/03/2024] Open
Abstract
BACKGROUND Adipose-derived stromal cells (ADSCs) demonstrate ability to promote tissue healing and down-regulate excessive inflammation. ADSCs have been used to treat critical limb ischemia in preclinical and clinical trials, but still, there is little known about their optimal delivery strategy. To date, no direct analysis of different methods of ADSCs delivery has been performed in the hindlimb ischemia model. Therefore, in this study we focused on the therapeutic efficacy of different ADSCs delivery methods in a murine model of hindlimb ischemia. METHODS For the hADSCs isolation, we used the subcutaneous adipose tissue collected during the surgery. The murine hindlimb ischemia was used as a model. The unilateral femoral artery ligation was performed on 10-12-week-old male C57BL/6. ADSCs were delivered directly into ischemic muscle, into the contralateral muscle or intravenously. 7 and 14 days after the surgery, the gastrocnemius and quadriceps muscles were collected for the immunohistochemical analysis. The results were analyzed with relevant tests using the Statistica software. RESULTS Our research revealed that muscle regeneration, angiogenesis, arteriogenesis and macrophage infiltration in murine model of hindlimb ischemia differ depending on ADSCs delivery method. We have demonstrated that intramuscular method (directly into ischemic limb) of ADSCs delivery is more efficient in functional recovery after critical limb ischemia than intravenous or contralateral route. CONCLUSIONS We have noticed that injection of ADSCs directly into ischemic limb is the optimal delivery strategy because it increases: (1) muscle fiber regeneration, (2) the number of capillaries and (3) the influx of macrophages F4/80+/CD206+.
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Affiliation(s)
- Ewelina Pilny
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Justyna Czapla
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Alina Drzyzga
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Ryszard Smolarczyk
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Sybilla Matuszczak
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Magdalena Jarosz-Biej
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Łukasz Krakowczyk
- Department of Oncologic and Reconstructive Surgery, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland
| | - Tomasz Cichoń
- Center for Translational Research and Molecular Biology of Cancer, Maria Skłodowska-Curie National Research Institute of Oncology, Gliwice Branch, Wybrzeże Armii Krajowej Street 15, 44-102, Gliwice, Poland.
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10
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Ren K, Vickers R, Murillo J, Ruparel NB. Revolutionizing orofacial pain management: the promising potential of stem cell therapy. FRONTIERS IN PAIN RESEARCH 2023; 4:1239633. [PMID: 38028430 PMCID: PMC10679438 DOI: 10.3389/fpain.2023.1239633] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2023] [Accepted: 09/22/2023] [Indexed: 12/01/2023] Open
Abstract
Orofacial pain remains a significant health issue in the United States. Pain originating from the orofacial region can be composed of a complex array of unique target tissue that contributes to the varying success of pain management. Long-term use of analgesic drugs includes adverse effects such as physical dependence, gastrointestinal bleeding, and incomplete efficacy. The use of mesenchymal stem cells for their pain relieving properties has garnered increased attention. In addition to the preclinical and clinical results showing stem cell analgesia in non-orofacial pain, studies have also shown promising results for orofacial pain treatment. Here we discuss the outcomes of mesenchymal stem cell treatment for pain and compare the properties of stem cells from different tissues of origin. We also discuss the mechanism underlying these analgesic/anti-nociceptive properties, including the role of immune cells and the endogenous opioid system. Lastly, advancements in the methods and procedures to treat patients experiencing orofacial pain with mesenchymal stem cells are also discussed.
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Affiliation(s)
- Ke Ren
- Department of Pain and Neural Sciences, University of Maryland, Baltimore, MD, United States
| | - Russel Vickers
- Clinical Stem Cells Pty Ltd., Sydney, NSW, Australia
- Oral Health Center, School of Dentistry, Faculty of Health and Behavioural Sciences, The University of Queensland, Brisbane, QLD, Australia
- Institute for Glycomics, Griffith University Queensland, Southport, QLD, Australia
| | - Josue Murillo
- Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
| | - Nikita B. Ruparel
- Department of Endodontics, University of Texas Health Science Center at San Antonio, San Antonio, TX, United States
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Xiong Z, An Q, Chen L, Xiang Y, Li L, Zheng Y. Cell or cell derivative-laden hydrogels for myocardial infarction therapy: from the perspective of cell types. J Mater Chem B 2023; 11:9867-9888. [PMID: 37751281 DOI: 10.1039/d3tb01411h] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 09/27/2023]
Abstract
Myocardial infarction (MI) is a global cardiovascular disease with high mortality and morbidity. To treat acute MI, various therapeutic approaches have been developed, including cells, extracellular vesicles, and biomimetic nanoparticles. However, the clinical application of these therapies is limited due to low cell viability, inadequate targetability, and rapid elimination from cardiac sites. Injectable hydrogels, with their three-dimensional porous structure, can maintain the biomechanical stabilization of hearts and the transplantation activity of cells. However, they cannot regenerate cardiomyocytes or repair broken hearts. A better understanding of the collaborative relationship between hydrogel delivery systems and cell or cell-inspired therapy will facilitate advancing innovative therapeutic strategies against MI. Following that, from the perspective of cell types, MI progression and recent studies on using hydrogel to deliver cell or cell-derived preparations for MI treatment are discussed. Finally, current challenges and future prospects of cell or cell derivative-laden hydrogels for MI therapy are proposed.
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Affiliation(s)
- Ziqing Xiong
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Qi An
- Department of Cardiovascular Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Liqiang Chen
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
| | - Yucheng Xiang
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
| | - Lian Li
- Key Laboratory of Drug-Targeting and Drug Delivery System of the Education Ministry and Sichuan Province, Sichuan Engineering Laboratory for Plant-Sourced Drug and Sichuan Research Center for Drug Precision Industrial Technology, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, China.
| | - Yaxian Zheng
- Department of Pharmacy, Affiliated Hospital of Southwest Jiaotong University, The Third People's Hospital of Chengdu, Chengdu, Sichuan, China.
- Institute of Biomedical Engineering, College of Medicine, Southwest Jiaotong University, Chengdu, Sichuan, China
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12
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Serretiello E, Ballini A, Smimmo A, Acunzo M, Raimo M, Cantore S, Di Domenico M. Extracellular Vesicles as a Translational Approach for the Treatment of COVID-19 Disease: An Updated Overview. Viruses 2023; 15:1976. [PMID: 37896755 PMCID: PMC10611252 DOI: 10.3390/v15101976] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2023] [Revised: 09/18/2023] [Accepted: 09/21/2023] [Indexed: 10/29/2023] Open
Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused a global pandemic in the years 2020-2022. With a high prevalence, an easy route of transmission, and a long incubation time, SARS-CoV-2 spread quickly and affected public health and socioeconomic conditions. Several points need to be elucidated about its mechanisms of infection, in particular, its capability to evade the immune system and escape from neutralizing antibodies. Extracellular vesicles (EVs) are phospholipid bilayer-delimited particles that are involved in cell-to-cell communication; they contain biological information such as miRNAs, proteins, nucleic acids, and viral components. Abundantly released from biological fluids, their dimensions are highly variable, which are used to divide them into exosomes (40 to 150 nm), microvesicles (40 to 10,000 nm), and apoptotic bodies (100-5000 nm). EVs are involved in many physiological and pathological processes. In this article, we report the latest evidence about EVs' roles in viral infections, focusing on the dual role of exosomes in promoting and inhibiting SARS-CoV-2 infection. The involvement of mesenchymal stromal/stem cells (MSCs) and MSC-derived EVs in COVID-19 treatment, such as the use of translational exosomes as a diagnostical/therapeutic approach, is also investigated. These elucidations could be useful to better direct the discovery of future diagnostical tools and new exosome-derived COVID-19 biomarkers, which can help achieve optimal therapeutic interventions and implement future vaccine strategies.
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Affiliation(s)
- Enrica Serretiello
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Andrea Ballini
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy
| | - Annafrancesca Smimmo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Marina Acunzo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Mariarosaria Raimo
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Stefania Cantore
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
| | - Marina Di Domenico
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli”, 80138 Naples, Italy; (E.S.); (A.S.); (M.A.); (M.R.); (S.C.); (M.D.D.)
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13
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Soni SS, D'Elia AM, Rodell CB. Control of the post-infarct immune microenvironment through biotherapeutic and biomaterial-based approaches. Drug Deliv Transl Res 2023; 13:1983-2014. [PMID: 36763330 PMCID: PMC9913034 DOI: 10.1007/s13346-023-01290-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/03/2023] [Indexed: 02/11/2023]
Abstract
Ischemic heart failure (IHF) is a leading cause of morbidity and mortality worldwide, for which heart transplantation remains the only definitive treatment. IHF manifests from myocardial infarction (MI) that initiates tissue remodeling processes, mediated by mechanical changes in the tissue (loss of contractility, softening of the myocardium) that are interdependent with cellular mechanisms (cardiomyocyte death, inflammatory response). The early remodeling phase is characterized by robust inflammation that is necessary for tissue debridement and the initiation of repair processes. While later transition toward an immunoregenerative function is desirable, functional reorientation from an inflammatory to reparatory environment is often lacking, trapping the heart in a chronically inflamed state that perpetuates cardiomyocyte death, ventricular dilatation, excess fibrosis, and progressive IHF. Therapies can redirect the immune microenvironment, including biotherapeutic and biomaterial-based approaches. In this review, we outline these existing approaches, with a particular focus on the immunomodulatory effects of therapeutics (small molecule drugs, biomolecules, and cell or cell-derived products). Cardioprotective strategies, often focusing on immunosuppression, have shown promise in pre-clinical and clinical trials. However, immunoregenerative therapies are emerging that often benefit from exacerbating early inflammation. Biomaterials can be used to enhance these therapies as a result of their intrinsic immunomodulatory properties, parallel mechanisms of action (e.g., mechanical restraint), or by enabling cell or tissue-targeted delivery. We further discuss translatability and the continued progress of technologies and procedures that contribute to the bench-to-bedside development of these critically needed treatments.
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Affiliation(s)
- Shreya S Soni
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
| | - Arielle M D'Elia
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA
| | - Christopher B Rodell
- School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA, 19104, USA.
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14
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Abubakar M, Masood MF, Javed I, Adil H, Faraz MA, Bhat RR, Fatima M, Abdelkhalek AM, Buccilli B, Raza S, Hajjaj M. Unlocking the Mysteries, Bridging the Gap, and Unveiling the Multifaceted Potential of Stem Cell Therapy for Cardiac Tissue Regeneration: A Narrative Review of Current Literature, Ethical Challenges, and Future Perspectives. Cureus 2023; 15:e41533. [PMID: 37551212 PMCID: PMC10404462 DOI: 10.7759/cureus.41533] [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] [Accepted: 07/06/2023] [Indexed: 08/09/2023] Open
Abstract
Revolutionary advancements in regenerative medicine have brought stem cell therapy to the forefront, offering promising prospects for the regeneration of ischemic cardiac tissue. Yet, its full efficacy, safety, and role in treating ischemic heart disease (IHD) remain limited. This literature review explores the intricate mechanisms underlying stem cell therapy. Furthermore, we unravel the innovative approaches employed to bolster stem cell survival, enhance differentiation, and seamlessly integrate them within the ischemic cardiac tissue microenvironment. Our comprehensive analysis uncovers how stem cells enhance cell survival, promote angiogenesis, and modulate the immune response. Stem cell therapy harnesses a multifaceted mode of action, encompassing paracrine effects and direct cell replacement. As our review progresses, we underscore the imperative for standardized protocols, comprehensive preclinical and clinical studies, and careful regulatory considerations. Lastly, we explore the integration of tissue engineering and genetic modifications, envisioning a future where stem cell therapy reigns supreme in regenerative medicine.
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Affiliation(s)
- Muhammad Abubakar
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
- Department of Internal Medicine, Siddique Sadiq Memorial Trust Hospital, Gujranwala, PAK
| | | | - Izzah Javed
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
| | - Hira Adil
- Department of Community Medicine, Khyber Girls Medical College, Hayatabad, PAK
| | - Muhammad Ahmad Faraz
- Department of Forensic Medicine, Post Graduate Medical Institute, Lahore General Hospital, Lahore, PAK
| | - Rakshita Ramesh Bhat
- Department of Medical Oncology, Mangalore Institute of Oncology, Mangalore, IND
- Department of Internal Medicine, Bangalore Medical College and Research Institute, Bangalore, IND
| | - Mahek Fatima
- Department of Internal Medicine, Osmania Medical College, Hyderabad, IND
| | | | - Barbara Buccilli
- Department of Human Neuroscience, Sapienza University of Rome, Rome, ITA
| | - Saud Raza
- Department of Internal Medicine, Ameer-Ud-Din Medical College, Lahore General Hospital, Lahore, PAK
| | - Mohsin Hajjaj
- Department of Internal Medicine, Jinnah Hospital Lahore, Lahore, PAK
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15
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Bouzazi D, Mami W, Mosbah A, Marrakchi N, Ben Ahmed M, Messadi E. Natriuretic-like Peptide Lebetin 2 Mediates M2 Macrophage Polarization in LPS-Activated RAW264.7 Cells in an IL-10-Dependent Manner. Toxins (Basel) 2023; 15:toxins15040298. [PMID: 37104236 PMCID: PMC10142756 DOI: 10.3390/toxins15040298] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2023] [Revised: 04/08/2023] [Accepted: 04/12/2023] [Indexed: 04/28/2023] Open
Abstract
Snake natriuretic peptide (NP) Lebetin 2 (L2) has been shown to improve cardiac function and reduce fibrosis as well as inflammation by promoting M2-type macrophages in a reperfused myocardial infarction (MI) model. However, the inflammatory mechanism of L2 remains unclear. Therefore, we investigated the effect of L2 on macrophage polarization in lipopolysaccharide (LPS)-activated RAW264.7 cells in vitro and explored the associated underlying mechanisms. TNF-α, IL-6 and IL-10 levels were assessed using an ELISA assay, and M2 macrophage polarization was determined by flow cytometry. L2 was used at non-cytotoxic concentrations determined by a preliminary MTT cell viability assay, and compared to B-type natriuretic peptide (BNP). In LPS-activated cells, both peptides reduced TNF-α and IL-6 release compared to controls. However, only L2 increased IL-10 release in a sustained manner and promoted downstream M2 macrophage polarization. Pretreatment of LPS-activated RAW264.7 cells with the selective NP receptor (NPR) antagonist isatin abolished both IL-10 and M2-like macrophage potentiation provided by L2. In addition, cell pretreatment with the IL-10 inhibitor suppressed L2-induced M2 macrophage polarization. We conclude that L2 exerts an anti-inflammatory response to LPS by regulating the release of inflammatory cytokines via stimulating of NP receptors and promoting M2 macrophage polarization through activation of IL-10 signaling.
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Affiliation(s)
- Dorsaf Bouzazi
- Plateforme de Physiologie et Physiopathologie Cardiovasculaires (P2C), Laboratoire des Biomolécules, Venins et Applications Théranostiques (LR20IPT01), Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
| | - Wael Mami
- Plateforme de Physiologie et Physiopathologie Cardiovasculaires (P2C), Laboratoire des Biomolécules, Venins et Applications Théranostiques (LR20IPT01), Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
| | - Amor Mosbah
- Laboratory of Biotechnology and Bio-Geo Resources Valorization (LR11ES31), Higher Institute of Biotechnology of Sidi Thabet (ISBST), University of Manouba, Tunis 2010, Tunisia
| | - Naziha Marrakchi
- Plateforme de Physiologie et Physiopathologie Cardiovasculaires (P2C), Laboratoire des Biomolécules, Venins et Applications Théranostiques (LR20IPT01), Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
| | - Melika Ben Ahmed
- Laboratoire de Transmission, Department of Clinical Immunology, Contrôle et Immunobiologie des Infections, Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
| | - Erij Messadi
- Plateforme de Physiologie et Physiopathologie Cardiovasculaires (P2C), Laboratoire des Biomolécules, Venins et Applications Théranostiques (LR20IPT01), Institut Pasteur de Tunis, Université Tunis El Manar, Tunis 1068, Tunisia
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16
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Yu X, Liu P, Li Z, Zhang Z. Function and mechanism of mesenchymal stem cells in the healing of diabetic foot wounds. Front Endocrinol (Lausanne) 2023; 14:1099310. [PMID: 37008908 PMCID: PMC10061144 DOI: 10.3389/fendo.2023.1099310] [Citation(s) in RCA: 35] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2022] [Accepted: 03/06/2023] [Indexed: 03/18/2023] Open
Abstract
Diabetes has become a global public health problem. Diabetic foot is one of the most severe complications of diabetes, which often places a heavy economic burden on patients and seriously affects their quality of life. The current conventional treatment for the diabetic foot can only relieve the symptoms or delay the progression of the disease but cannot repair damaged blood vessels and nerves. An increasing number of studies have shown that mesenchymal stem cells (MSCs) can promote angiogenesis and re-epithelialization, participate in immune regulation, reduce inflammation, and finally repair diabetic foot ulcer (DFU), rendering it an effective means of treating diabetic foot disease. Currently, stem cells used in the treatment of diabetic foot are divided into two categories: autologous and allogeneic. They are mainly derived from the bone marrow, umbilical cord, adipose tissue, and placenta. MSCs from different sources have similar characteristics and subtle differences. Mastering their features to better select and use MSCs is the premise of improving the therapeutic effect of DFU. This article reviews the types and characteristics of MSCs and their molecular mechanisms and functions in treating DFU to provide innovative ideas for using MSCs to treat diabetic foot and promote wound healing.
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Affiliation(s)
- Xiaoping Yu
- School of Medicine and Nursing, Chengdu University, Chengdu, Sichuan, China
| | - Pan Liu
- Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China
| | - Zheng Li
- People’s Hospital of Jiulongpo District, Chongqing, China
| | - Zhengdong Zhang
- School of Clinical Medicine, Chengdu Medical College, Chengdu, Sichuan, China
- Department of Orthopedics, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan, China
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17
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Menasché P. Mesenchymal Stromal Cell Therapy for Heart Failure: Never Stop DREAMing. J Am Coll Cardiol 2023; 81:864-866. [PMID: 36858706 DOI: 10.1016/j.jacc.2022.12.019] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/13/2022] [Accepted: 12/19/2022] [Indexed: 03/03/2023]
Affiliation(s)
- Philippe Menasché
- Department of Cardiovascular Surgery, Hôpital Européen Georges Pompidou, AP-HP, Université Paris Cité, Inserm, PARCC, Paris, France.
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18
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Shuster-Hyman H, Siddiqui F, Gallagher D, Gauthier-Fisher A, Librach CL. Time course and mechanistic analysis of human umbilical cord perivascular cell mitigation of lipopolysaccharide-induced systemic and neurological inflammation. Cytotherapy 2023; 25:125-137. [PMID: 36473795 DOI: 10.1016/j.jcyt.2022.10.014] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Revised: 10/11/2022] [Accepted: 10/20/2022] [Indexed: 12/12/2022]
Abstract
BACKGROUND AIMS Because of their potent immunomodulatory and anti-inflammatory properties, mesenchymal stromal cells are a major focus in the field of stem cell therapy. However, the precise mechanisms underlying this are not entirely understood. Human umbilical cord perivascular cells (HUCPVCs) are a promising cell therapy candidate. This study was designed to evaluate the time course and mechanisms by which HUCPVCs mitigate lipopolysaccharide (LPS)-induced systemic and neurological inflammation in immunocompetent mice. To explore the underlying mechanisms, the authors investigated the biodistribution and fate of HUCPVCs. METHODS Male C57BL/6 mice were randomly allocated to four groups: control, LPS, HUCPVCs or LPS + HUCPVCs. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and cytokine arrays were used to assess changes in pro-inflammatory mediators systemically and in the brain. Depressive-like behavioral changes were evaluated via a forced swim test. Quantum dot (qDot) labeling and immunohistochemistry were used to assess the biodistribution and fate of HUCPVCs and interactions with recipient innate immune cells. RESULTS A single intravenously delivered dose of HUCPVCs significantly reduced the systemic inflammation induced by LPS within the first 24 h after administration. HUCPVC treatment abrogated the upregulated expression of pro-inflammatory genes in the hippocampus and cortex and attenuated depressive-like behavior induced by LPS treatment. Biodistribution analysis revealed that HUCPVC-derived qDots rapidly accumulated in the lungs and demonstrated limited in vivo persistence. Furthermore, qDot signals were associated with major recipient innate immune cells and promoted a shift in macrophages toward a regulatory phenotype in the lungs. CONCLUSIONS Overall, this study demonstrates that HUCPVCs can successfully reduce systemic and neurological inflammation induced by LPS within the first 24 h after administration. Biodistribution and fate analyses suggest a critical role for the innate immune system in the HUCPVC-based immunomodulation mechanism.
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Affiliation(s)
- Hannah Shuster-Hyman
- CReATe Fertility Center, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada
| | | | | | | | - Clifford L Librach
- CReATe Fertility Center, Toronto, Ontario, Canada; Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada; Department of Obstetrics and Gynecology, University of Toronto, Toronto, Ontario, Canada; Department of Physiology, University of Toronto, Toronto, Ontario, Canada.
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19
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Mesenchymal Stem Cells and Their Exocytotic Vesicles. Int J Mol Sci 2023; 24:ijms24032085. [PMID: 36768406 PMCID: PMC9916886 DOI: 10.3390/ijms24032085] [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: 12/28/2022] [Revised: 01/16/2023] [Accepted: 01/18/2023] [Indexed: 01/21/2023] Open
Abstract
Mesenchymal stem cells (MSCs), as a kind of pluripotent stem cells, have attracted much attention in orthopedic diseases, geriatric diseases, metabolic diseases, and sports functions due to their osteogenic potential, chondrogenic differentiation ability, and adipocyte differentiation. Anti-inflammation, anti-fibrosis, angiogenesis promotion, neurogenesis, immune regulation, and secreted growth factors, proteases, hormones, cytokines, and chemokines of MSCs have been widely studied in liver and kidney diseases, cardiovascular and cerebrovascular diseases. In recent years, many studies have shown that the extracellular vesicles of MSCs have similar functions to MSCs transplantation in all the above aspects. Here we review the research progress of MSCs and their exocrine vesicles in recent years.
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20
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Feng Q, Li Q, Zhou H, Sun L, Lin C, Jin Y, Wang D, Guo G. The role of major immune cells in myocardial infarction. Front Immunol 2023; 13:1084460. [PMID: 36741418 PMCID: PMC9892933 DOI: 10.3389/fimmu.2022.1084460] [Citation(s) in RCA: 17] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2022] [Accepted: 12/19/2022] [Indexed: 01/20/2023] Open
Abstract
Myocardial infarction (MI) is a cardiovascular disease (CVD) with high morbidity and mortality worldwide, often leading to adverse cardiac remodeling and heart failure, which is a serious threat to human life and health. The immune system makes an important contribution to the maintenance of normal cardiac function. In the disease process of MI, necrotic cardiomyocytes release signals that activate nonspecific immunity and trigger the action of specific immunity. Complex immune cells play an important role in all stages of MI progression by removing necrotic cardiomyocytes and tissue and promoting the healing of damaged tissue cells. With the development of biomaterials, cardiac patches have become an emerging method of repairing MI, and the development of engineered cardiac patches through the construction of multiple animal models of MI can help treat MI. This review introduces immune cells involved in the development of MI, summarizes the commonly used animal models of MI and the newly developed cardiac patch, so as to provide scientific reference for the accurate diagnosis and effective treatment of MI.
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Affiliation(s)
- Qiang Feng
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China,Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Qirong Li
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Hengzong Zhou
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China
| | - Liqun Sun
- Department of Pathogenobiology, Jilin University Mycology Research Center, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Chao Lin
- School of Grain Science and Technology, Jilin Business and Technology College, Changchun, China
| | - Ye Jin
- School of Pharmacy, Changchun University of Chinese Medicine, Changchun, China
| | - Dongxu Wang
- Laboratory Animal Center, College of Animal Science, Jilin University, Changchun, China,*Correspondence: Gongliang Guo,
| | - Gongliang Guo
- Department of Cardiology, China-Japan Union Hospital of Jilin University, Changchun, China,*Correspondence: Gongliang Guo,
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21
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Balaji Easwaran V, Satarker S, V Gujaran T, John J, Veedu AP, George KT, Purayil DK, Beegum F, Mathew A, Vibhavari R, Chaudhari SS, Pai KSR. Expediting Molecular Translational Approach of Mesenchymal Stem Cells in COVID-19 Treatment. Curr Stem Cell Res Ther 2023; 18:653-675. [PMID: 36424799 DOI: 10.2174/1574888x18666221124122113] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2022] [Revised: 09/20/2022] [Accepted: 09/30/2022] [Indexed: 11/27/2022]
Abstract
Coronavirus disease (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 with severe respiratory failure and organ damage that later appeared as a pandemic disease. Worldwide, people's mental and physical health and socioeconomic have been affected. Currently, with no promising treatment for COVID-19, the existing anti-viral drugs and vaccines are the only hope to boost the host immune system to reduce morbidity and mortality rate. Unfortunately, several reports show that people who are partially or fully vaccinated are still susceptible to COVID-19 infection. Evidence suggests that COVID-19 immunopathology may include dysregulation of macrophages and monocytes, reduced type 1 interferons (IFN-1), and enhanced cytokine storm that results in hypersecretion of proinflammatory cytokines, capillary leak syndrome, intravascular coagulation, and acute respiratory distress syndrome (ARDS) ultimately leading to the worsening of patient's condition and death in most cases. The recent use of cell-based therapies such as mesenchymal stem cells (MSCs) for critically ill COVID-19 patients has been authorized by the Food and Drug Administration (FDA) to alleviate cytokine release syndrome. It protects the alveolar epithelial cells by promoting immunomodulatory action and secreting therapeutic exosomes to improve lung function and attenuate respiratory failure. As a result, multiple clinical trials have been registered using MSCs that aim to use various cell sources, and dosages to promote safety and efficacy against COVID-19 infection. In this review, the possibility of using MSCs in COVID-19 treatment and its associated challenges in their use have been briefly discussed.
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Affiliation(s)
- Vignesh Balaji Easwaran
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Sairaj Satarker
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Tanvi V Gujaran
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Jeena John
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Anuranjana Putiya Veedu
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Krupa Thankam George
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Divya Kunhi Purayil
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Fathima Beegum
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Anna Mathew
- Department of Pharmacognosy, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Rja Vibhavari
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - Sneha Sunil Chaudhari
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
| | - K Sreedhara Ranganath Pai
- Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal-576104, Karnataka, India
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22
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Ling S, You Z, Li Y, Zhang J, Zhao S, He Y, Chen X. The role of γδ T17 cells in cardiovascular disease. J Leukoc Biol 2022; 112:1649-1661. [PMID: 36073777 DOI: 10.1002/jlb.3mr0822-761rr] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2022] [Revised: 06/23/2022] [Accepted: 08/03/2022] [Indexed: 01/04/2023] Open
Abstract
Due to the ability of γδ T cells to bridge adaptive and innate immunity, γδ T cells can respond to a variety of molecular cues and acquire the ability to induce a variety of cytokines such as IL-17 family, IFN-γ, IL-4, and IL-10. IL-17+ γδ T cells (γδ T17 cells) populations have recently received considerable interest as they are the major early source of IL-17A in many immune response models. However, the exact mechanism of γδ T17 cells is still poorly understood, especially in the context of cardiovascular disease (CVD). CVD is the leading cause of death in the world, and it tends to be younger. Here, we offer a review of the cardiovascular inflammatory and immune functions of γδ T17 cells in order to understand their role in CVD, which may be the key to developing new clinical applications.
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Affiliation(s)
- Shaoxue Ling
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Zonghao You
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Yang Li
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Jian Zhang
- School of Chinese Materia Medica, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Shuwu Zhao
- School of Intergrative Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Yongzhi He
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
| | - Xi Chen
- College of Pharmaceutical Engineering of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyanghu Road, Tianjin, 301617, China
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Hoang DM, Pham PT, Bach TQ, Ngo ATL, Nguyen QT, Phan TTK, Nguyen GH, Le PTT, Hoang VT, Forsyth NR, Heke M, Nguyen LT. Stem cell-based therapy for human diseases. Signal Transduct Target Ther 2022; 7:272. [PMID: 35933430 PMCID: PMC9357075 DOI: 10.1038/s41392-022-01134-4] [Citation(s) in RCA: 455] [Impact Index Per Article: 151.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 07/19/2022] [Accepted: 07/21/2022] [Indexed: 02/07/2023] Open
Abstract
Recent advancements in stem cell technology open a new door for patients suffering from diseases and disorders that have yet to be treated. Stem cell-based therapy, including human pluripotent stem cells (hPSCs) and multipotent mesenchymal stem cells (MSCs), has recently emerged as a key player in regenerative medicine. hPSCs are defined as self-renewable cell types conferring the ability to differentiate into various cellular phenotypes of the human body, including three germ layers. MSCs are multipotent progenitor cells possessing self-renewal ability (limited in vitro) and differentiation potential into mesenchymal lineages, according to the International Society for Cell and Gene Therapy (ISCT). This review provides an update on recent clinical applications using either hPSCs or MSCs derived from bone marrow (BM), adipose tissue (AT), or the umbilical cord (UC) for the treatment of human diseases, including neurological disorders, pulmonary dysfunctions, metabolic/endocrine-related diseases, reproductive disorders, skin burns, and cardiovascular conditions. Moreover, we discuss our own clinical trial experiences on targeted therapies using MSCs in a clinical setting, and we propose and discuss the MSC tissue origin concept and how MSC origin may contribute to the role of MSCs in downstream applications, with the ultimate objective of facilitating translational research in regenerative medicine into clinical applications. The mechanisms discussed here support the proposed hypothesis that BM-MSCs are potentially good candidates for brain and spinal cord injury treatment, AT-MSCs are potentially good candidates for reproductive disorder treatment and skin regeneration, and UC-MSCs are potentially good candidates for pulmonary disease and acute respiratory distress syndrome treatment.
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Affiliation(s)
- Duc M Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam.
| | - Phuong T Pham
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trung Q Bach
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Anh T L Ngo
- Department of Cellular Therapy, Vinmec High-Tech Center, Vinmec Healthcare System, Hanoi, Vietnam
| | - Quyen T Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Trang T K Phan
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Giang H Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Phuong T T Le
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Van T Hoang
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
| | - Nicholas R Forsyth
- Institute for Science & Technology in Medicine, Keele University, Keele, UK
| | - Michael Heke
- Department of Biology, Stanford University, Stanford, CA, USA
| | - Liem Thanh Nguyen
- Department of Research and Development, Vinmec Research Institute of Stem Cell and Gene Technology, Vinmec Healthcare System, Hanoi, Vietnam
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Macrophage bioassay standardization to assess the anti-inflammatory activity of mesenchymal stromal cell-derived small extracellular vesicles. Cytotherapy 2022; 24:999-1012. [PMID: 35798638 DOI: 10.1016/j.jcyt.2022.05.011] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/23/2022] [Accepted: 05/30/2022] [Indexed: 12/18/2022]
Abstract
BACKGROUND AIMS Owing to the lack of biological assays, determining the biological activity of extracellular vesicles has proven difficult. Here the authors standardized an in vitro assay to assess the anti-inflammatory activity of mesenchymal stromal cell-derived small extracellular vesicles (MSC-sEVs) based on their ability to prevent acquisition of the M1 phenotype in lipopolysaccharide (LPS)-stimulated RAW 264.7 macrophages. Induction of tumor necrosis factor alpha, IL-1β, IL-6 and inducible nitric oxide synthase (iNOS) characterizes the M1 phenotype. Nitric oxide released by iNOS turns into nitrite, which can be easily quantitated in culture media by Griess reaction. METHODS The authors first tested different assay conditions in 96-well plates, including two seeding densities (2 × 104 cells/well and 4 × 104 cells/well), four LPS doses (1 ng/mL, 10 ng/mL, 100 ng/mL and 1000 ng/mL) and two time points (16 h and 24 h), in order to determine the best set-up to accurately measure nitrite concentration as an index of M1 macrophage polarization. RESULTS The authors found that seeding 2 × 104 cells/well and stimulating with 10 ng/mL LPS for 16 h allowed the inhibition of nitrite production by 60% with the use of dexamethasone. Using these established conditions, the authors were able to test different MSC-sEV preparations and generate dose-response curves. Moreover, the authors fully analytically validated assay performance and fulfilled cross-validation against other M1 markers. CONCLUSIONS The authors standardized a quick, cheap and reproducible in vitro macrophage assay that allows for the evaluation and estimation of the anti-inflammatory activity of MSC-sEVs.
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Handley EL, Callanan A. Modulation of Tissue Microenvironment Following Myocardial Infarction. ADVANCED NANOBIOMED RESEARCH 2022. [DOI: 10.1002/anbr.202200005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/10/2022] Open
Affiliation(s)
- Ella Louise Handley
- Institute for Bioengineering School of Engineering University of Edinburgh Edinburgh EH9 3DW UK
| | - Anthony Callanan
- Institute for Bioengineering School of Engineering University of Edinburgh Edinburgh EH9 3DW UK
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Wang D, Wen JY, Wu D, Ying ZY, Wen ZM, Peng HQ, Geng C, Feng YB, Sui ZG, Lv HY, Wu J, Xu B. LPS-pretreated MSC-conditioned medium optimized with 10-kDa filter attenuates the injury of H9c2 cardiomyocytes in a model of hypoxia/reoxygenation. Can J Physiol Pharmacol 2022; 100:651-664. [PMID: 35533248 DOI: 10.1139/cjpp-2021-0745] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Mesenchymal stem cell-derived conditioned medium (MSC-CM) improves cardiac function, which is partly attributed to released paracrine factors. Since such cardioprotection is moderate and transient, it's essential to optimize MSC-CM effective components to alleviate myocardial injury. To optimize MSC-CM, MSCs were treated with or without lipopolysaccharides (LPSs) for 48 h (serum-free), and the supernatant was collected. Then, LPS-CM (MSC stimulated by LPS) was further treated with LPS remover (LPS Re-CM) or was concentrated with a 10-kDa cutoff filter (10 kDa-CM). ELISA showed that all pretreatments increased levels of VEGF, HGF, and IGF except LPS remover; 10 kDa-CM was superior to other-CM. CCK-8 displayed that viability of injured H9c2 cells enhanced with the increase of MSC-CM concentration. We also found 10 kDa-CM significantly alleviated H9c2 hypoxia/reoxygenation (H/R) injury, as evidenced by increased Bcl-2/Bax ratio, decreased the levels of LDH and cTn. TEM, TUNEL, and H&E staining confirmed 10 kDa-CM inhibited H/R-induced H9c2 morphological changes. Proteomic analysis identified 41 differentially expressed proteins in 10 kDa-CM, among which anti-inflammation, pro-angiogenesis, and anti-apoptosis were related to cardiac protection. This study indicates that 10 kDa-CM protects H9c2 cardiomyocytes from H/R injury by preserving most of the protective factors, such as VEGF, HGF, and IGF, in MSC-CM.
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Affiliation(s)
- Dan Wang
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China.,Ordos Central Hospital, 586048, Department of Pharmacy, Ordos, Inner Mongolia, China;
| | - Jing-Yi Wen
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China;
| | - Di Wu
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China;
| | - Zi-Yue Ying
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China;
| | - Zhi-Min Wen
- The Second Affiliated Hospital of Dalian Medical University, Department of Clinical Laboratory, Dalian, Liaoning, China;
| | - Hui-Qian Peng
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China;
| | - Cong Geng
- The Second Affiliated Hospital of Dalian Medical University, Department of Clinical Laboratory, Dalian, Liaoning, China;
| | - Yuan-Bo Feng
- KU Leuven University Hospitals Leuven, 60182, Leuven, Flanders, Belgium;
| | - Zhi-Gang Sui
- Chinese Academy of Science, Dalian, Liaoning, China;
| | - Hui-Yi Lv
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China;
| | - Jun Wu
- The Second Affiliated Hospital of Dalian Medical University, Department of Echocardiography, Dalian, Liaoning, China;
| | - Bing Xu
- The Second Affiliated Hospital of Dalian Medical University, Department of Pharmacy, Dalian, Liaoning, China, 116023;
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Tracy EP, Stielberg V, Rowe G, Benson D, Nunes SS, Hoying JB, Murfee WL, LeBlanc AJ. State of the field: cellular and exosomal therapeutic approaches in vascular regeneration. Am J Physiol Heart Circ Physiol 2022; 322:H647-H680. [PMID: 35179976 PMCID: PMC8957327 DOI: 10.1152/ajpheart.00674.2021] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 02/07/2022] [Accepted: 02/09/2022] [Indexed: 01/19/2023]
Abstract
Pathologies of the vasculature including the microvasculature are often complex in nature, leading to loss of physiological homeostatic regulation of patency and adequate perfusion to match tissue metabolic demands. Microvascular dysfunction is a key underlying element in the majority of pathologies of failing organs and tissues. Contributing pathological factors to this dysfunction include oxidative stress, mitochondrial dysfunction, endoplasmic reticular (ER) stress, endothelial dysfunction, loss of angiogenic potential and vascular density, and greater senescence and apoptosis. In many clinical settings, current pharmacologic strategies use a single or narrow targeted approach to address symptoms of pathology rather than a comprehensive and multifaceted approach to address their root cause. To address this, efforts have been heavily focused on cellular therapies and cell-free therapies (e.g., exosomes) that can tackle the multifaceted etiology of vascular and microvascular dysfunction. In this review, we discuss 1) the state of the field in terms of common therapeutic cell population isolation techniques, their unique characteristics, and their advantages and disadvantages, 2) common molecular mechanisms of cell therapies to restore vascularization and/or vascular function, 3) arguments for and against allogeneic versus autologous applications of cell therapies, 4) emerging strategies to optimize and enhance cell therapies through priming and preconditioning, and, finally, 5) emerging strategies to bolster therapeutic effect. Relevant and recent clinical and animal studies using cellular therapies to restore vascular function or pathologic tissue health by way of improved vascularization are highlighted throughout these sections.
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Affiliation(s)
- Evan Paul Tracy
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Virginia Stielberg
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
| | - Daniel Benson
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
- Department of Bioengineering, University of Louisville, Louisville, Kentucky
| | - Sara S Nunes
- Toronto General Hospital Research Institute, University Health Network, Toronto, Ontario, Canada
- Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada
- Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
- Heart & Stroke/Richard Lewar Centre of Excellence, University of Toronto, Toronto, Ontario, Canada
| | - James B Hoying
- Advanced Solutions Life Sciences, Manchester, New Hampshire
| | - Walter Lee Murfee
- J. Crayton Pruitt Family Department of Biomedical Engineering, University of Florida, Gainesville, Florida
| | - Amanda Jo LeBlanc
- Cardiovascular Innovation Institute and the Department of Physiology, University of Louisville, Louisville, Kentucky
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28
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Kim MJ, Moon W, Heo J, Lim S, Lee SH, Jeong JY, Lee SJ. Optimization of adipose tissue-derived mesenchymal stromal cells transplantation for bone marrow repopulation following irradiation. World J Stem Cells 2022; 14:245-263. [PMID: 35432736 PMCID: PMC8968216 DOI: 10.4252/wjsc.v14.i3.245] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 01/12/2022] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Bone marrow (BM) suppression is one of the most common side effects of radiotherapy and the primary cause of death following exposure to irradiation. Despite concerted efforts, there is no definitive treatment method available. Recent studies have reported using mesenchymal stromal cells (MSCs), but their therapeutic effects are contested. AIM We administered and examined the effects of various amounts of adipose-derived MSCs (ADSCs) in mice with radiation-induced BM suppression. METHODS Mice were divided into three groups: Normal control group, irradiated (RT) group, and stem cell-treated group following whole-body irradiation (WBI). Mouse ADSCs (mADSCs) were transplanted into the peritoneal cavity either once or three times at 5 × 105 cells/200 μL. The white blood cell count and the levels of, plasma cytokines, BM mRNA, and BM surface markers were compared between the three groups. Human BM-derived CD34+ hematopoietic progenitor cells were co-cultured with human ADSCs (hADSCs) or incubated in the presence of hADSCs conditioned media to investigate the effect on human cells in vitro. RESULTS The survival rate of mice that received one transplant of mADSCs was higher than that of mice that received three transplants. Multiple transplantations of ADSCs delayed the repopulation of BM hematopoietic stem cells. Anti-inflammatory effects and M2 polarization by intraperitoneal ADSCs might suppress erythropoiesis and induce myelopoiesis in sub-lethally RT mice. CONCLUSION The results suggested that an optimal amount of MSCs could improve survival rates post-WBI.
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Affiliation(s)
- Min-Jung Kim
- Department of Biochemistry, Cancer Research Institute Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Won Moon
- Department of Internal Medicine, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Jeonghoon Heo
- Department of Molecular Biology and Immunology, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Sangwook Lim
- Department of Radiation Oncology, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Seung-Hyun Lee
- Department of General Surgery, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Jee-Yeong Jeong
- Department of Biochemistry, Cancer Research Institute Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea
| | - Sang Joon Lee
- Department of Ophthalmology, Gospel Hospital, Kosin University College of Medicine, Seo-gu 49267, Busan, South Korea.
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Xue J, Gao J, Gu Y, Wang A, Yu S, Li B, Yin Y, Wang J, Su W, Zhang H, Ren W, Gu W, Lv Z, Mu Y, Cheng Y. Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes. Stem Cell Res Ther 2022; 13:109. [PMID: 35313972 PMCID: PMC8935757 DOI: 10.1186/s13287-022-02791-6] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2021] [Accepted: 01/28/2022] [Indexed: 11/22/2022] Open
Abstract
Background Previous research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement.
Methods We induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy. Results UC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen. Conclusions Our results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future. Supplementary Information The online version contains supplementary material available at 10.1186/s13287-022-02791-6.
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Affiliation(s)
- Jing Xue
- Medical School of Chinese PLA, Beijing, China.,Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.,Department of Endocrinology, Diabetes Center of People's Liberation Army (PLA), PLA Strategic Support Force Characteristic Medical Center (The 306th Hospital of PLA), Beijing, China
| | - Jieqing Gao
- Department of Endocrinology, Beijing Rehabilitation Hospital, Capital Medical University, Beijing, China
| | - Yulin Gu
- Medical School of Chinese PLA, Beijing, China.,Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Aihong Wang
- Department of Endocrinology, Diabetes Center of People's Liberation Army (PLA), PLA Strategic Support Force Characteristic Medical Center (The 306th Hospital of PLA), Beijing, China
| | - Songyan Yu
- Department of Endocrinology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Bing Li
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yaqi Yin
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Jie Wang
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Wanlu Su
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.,School of Medicine, Nankai University, Tianjin, China
| | - Haixia Zhang
- Medical School of Chinese PLA, Beijing, China.,Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weizheng Ren
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Weijun Gu
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Zhaohui Lv
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China
| | - Yiming Mu
- Medical School of Chinese PLA, Beijing, China. .,Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
| | - Yu Cheng
- Department of Endocrinology, The First Medical Center of Chinese PLA General Hospital, Beijing, China.
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Dang J, Yang J, Yu Z, Chen L, Zhang Z, Wang K, Tang J, Yi C. Bone marrow mesenchymal stem cells enhance angiogenesis and promote fat retention in fat grafting via polarized macrophages. Stem Cell Res Ther 2022; 13:52. [PMID: 35120568 PMCID: PMC8817529 DOI: 10.1186/s13287-022-02709-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Accepted: 01/09/2022] [Indexed: 11/30/2022] Open
Abstract
Background Fat grafting is one of the most common soft tissue filling methods in plastic surgery. Bone marrow mesenchymal stem cell (BM-MSC) transplantation is an effective method for improving graft retention. However, the role of BM-MSCs in fat transplantation is not completely clear. Methods Human fat particles, together with BM-MSCs or PBS as a control, were subcutaneously transplanted into the backs of nude mice. Samples were taken on days 14, 30 and 90 post-grafting to calculate the fat graft retention rate, and tissue staining was evaluated. Furthermore, macrophages were treated with BM-MSC conditioned medium (BM-MSC-CM) to identify the beneficial component secreted by these stem cells. Results In this study, we found that BM-MSCs improved retention by enhancing angiogenesis in fat grafting. Further analysis revealed that BM-MSCs could significantly inhibit the expression of the proinflammatory M1 macrophage markers interleukin (IL)-1β, tumor necrosis factor-α (TNF-α) and IL-6 in the early stages of fat grafting and promote the expression of the anti-inflammatory M2 macrophage markers Arg1, IL-10 and VEGF. Furthermore, our results showed that IL-10 secreted by BM-MSCs induced M2 macrophage polarization in vitro. Conclusions BM-MSC transplantation can improve the fat retention rate and promote angiogenesis, which may be related to M2 macrophages. These results help elucidate the role of BM-MSCs in fat grafting.
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Affiliation(s)
- Juanli Dang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jizhong Yang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhou Yu
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Lin Chen
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Zhaoxiang Zhang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Kai Wang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Jiezhang Tang
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China
| | - Chenggang Yi
- Department of Plastic and Reconstructive Surgery, Xijing Hospital, Fourth Military Medical University, Xi'an, China. .,Department of Plastic Surgery, The Second Affiliated Hospital, Medical School, Zhejiang University, Hangzhou, China.
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Sharma A, Gupta S, Archana S, Verma RS. Emerging Trends in Mesenchymal Stem Cells Applications for Cardiac Regenerative Therapy: Current Status and Advances. Stem Cell Rev Rep 2022; 18:1546-1602. [PMID: 35122226 DOI: 10.1007/s12015-021-10314-8] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/29/2021] [Indexed: 12/29/2022]
Abstract
Irreversible myocardium infarction is one of the leading causes of cardiovascular disease (CVD) related death and its quantum is expected to grow in coming years. Pharmacological intervention has been at the forefront to ameliorate injury-related morbidity and mortality. However, its outcomes are highly skewed. As an alternative, stem cell-based tissue engineering/regenerative medicine has been explored quite extensively to regenerate the damaged myocardium. The therapeutic modality that has been most widely studied both preclinically and clinically is based on adult multipotent mesenchymal stem cells (MSC) delivered to the injured heart. However, there is debate over the mechanistic therapeutic role of MSC in generating functional beating cardiomyocytes. This review intends to emphasize the role and use of MSC in cardiac regenerative therapy (CRT). We have elucidated in detail, the various aspects related to the history and progress of MSC use in cardiac tissue engineering and its multiple strategies to drive cardiomyogenesis. We have further discussed with a focus on the various therapeutic mechanism uncovered in recent times that has a significant role in ameliorating heart-related problems. We reviewed recent and advanced technologies using MSC to develop/create tissue construct for use in cardiac regenerative therapy. Finally, we have provided the latest update on the usage of MSC in clinical trials and discussed the outcome of such studies in realizing the full potential of MSC use in clinical management of cardiac injury as a cellular therapy module.
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Affiliation(s)
- Akriti Sharma
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India
| | - Santosh Gupta
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India
| | - S Archana
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India
| | - Rama Shanker Verma
- Stem Cell and Molecular Biology Laboratory, Bhupat and Jyoti Mehta School of Biosciences, Department of Biotechnology, Indian Institute of Technology-Madras, Chennai, 600036, Tamil Nadu, India.
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Wang Y, Qi Z, Yan Z, Ji N, Yang X, Gao D, Hu L, Lv H, Zhang J, Li M. Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease. Front Cell Dev Biol 2022; 9:742088. [PMID: 35096808 PMCID: PMC8790228 DOI: 10.3389/fcell.2021.742088] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 12/14/2021] [Indexed: 12/12/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are the member of multipotency stem cells, which possess the capacity for self-renewal and multi-directional differentiation, and have several characteristics, including multi-lineage differentiation potential and immune regulation, which make them a promising source for cell therapy in inflammation, immune diseases, and organ transplantation. In recent years, MSCs have been described as a novel therapeutic strategy for the treatment of cardiovascular diseases because they are potent modulators of immune system with the ability to modulating immune cell subsets, coordinating local and systemic innate and adaptive immune responses, thereby enabling the formation of a stable inflammatory microenvironment in damaged cardiac tissues. In this review, the immunoregulatory characteristics and potential mechanisms of MSCs are sorted out, the effect of these MSCs on immune cells is emphasized, and finally the application of this mechanism in the treatment of cardiovascular diseases is described to provide help for clinical application.
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Affiliation(s)
- Yueyao Wang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China.,National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, Tianjin, China
| | - Zhongwen Qi
- Institute of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhipeng Yan
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Nan Ji
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Xiaoya Yang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Dongjie Gao
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Leilei Hu
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Hao Lv
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Junping Zhang
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Meng Li
- First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
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Hopes and Hurdles of Employing Mesenchymal Stromal Cells in the Treatment of Cardiac Fibrosis. Int J Mol Sci 2021; 22:ijms222313000. [PMID: 34884805 PMCID: PMC8657815 DOI: 10.3390/ijms222313000] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 11/25/2021] [Accepted: 11/29/2021] [Indexed: 12/04/2022] Open
Abstract
Excessive cardiac fibrosis plays a crucial role in almost all types of heart disease. Generally, cardiac fibrosis is a scarring process triggered in response to stress, injury, or aging and is characterized by the accumulation of activated myofibroblasts that deposit high levels of extracellular matrix proteins in the myocardium. While it is beneficial for cardiac repair in the short term, it can also result in pathological remodeling, tissue stiffening, and cardiac dysfunction, contributing to the progression of heart failure, arrhythmia, and sudden cardiac death. Despite its high prevalence, there is a lack of effective and safe therapies that specifically target myofibroblasts to inhibit or even reverse pathological cardiac fibrosis. In the past few decades, cell therapy has been under continuous evaluation as a potential treatment strategy, and several studies have shown that transplantation of mesenchymal stromal cells (MSCs) can reduce cardiac fibrosis and improve heart function. Mechanistically, it is believed that the heart benefits from MSC therapy by stimulating innate anti-fibrotic and regenerative reactions. The mechanisms of action include paracrine signaling and cell-to-cell interactions. In this review, we provide an overview of the anti-fibrotic properties of MSCs and approaches to enhance them and discuss future directions of MSCs for the treatment of cardiac fibrosis.
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Dymowska M, Aksamit A, Zielniok K, Kniotek M, Kaleta B, Roszczyk A, Zych M, Dabrowski F, Paczek L, Burdzinska A. Interaction between Macrophages and Human Mesenchymal Stromal Cells Derived from Bone Marrow and Wharton's Jelly-A Comparative Study. Pharmaceutics 2021; 13:pharmaceutics13111822. [PMID: 34834238 PMCID: PMC8624657 DOI: 10.3390/pharmaceutics13111822] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2021] [Revised: 10/27/2021] [Accepted: 10/28/2021] [Indexed: 01/15/2023] Open
Abstract
Despite intensive clinical research on the use of mesenchymal stromal cells (MSCs), further basic research in this field is still required. Herein, we compared human bone marrow MSCs (BM-MSCs, n = 6) and Wharton’s jelly MSCs (WJ-MSCs, n = 6) in their ability to interact with human primary macrophages. Evaluation of secretory potential revealed that under pro-inflammatory stimulation, WJ-MSCs secreted significantly more IL-6 than BM-MSCs (2-fold). This difference did not translate into the effect of MSCs on macrophages: both types of MSCs significantly directed M1-like macrophages toward the M2 phenotype (based on CD206 expression) to a similar extent. This observation was consistent both in flow cytometry analysis and immunocytochemical assessment. The effect of MSCs on macrophages was sustained when IL-6 signaling was blocked with Tocilizumab. Macrophages, regardless of polarization status, enhanced chemotaxis of both BM-MSCs and WJ-MSCs (p < 0.01; trans-well assay), with WJ-MSCs being significantly more responsive to M1-derived chemotactic signals than BM-MSCs. Furthermore, WJ-MSCs increased their motility (scratch assay) when exposed to macrophage-conditioned medium while BM-MSCs did not. These results indicate that although both BM-MSCs and WJ-MSCs have the ability to reciprocally interact with macrophages, the source of MSCs could slightly but significantly modify the response under clinical settings.
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Affiliation(s)
- Marta Dymowska
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Laboratory of Cell Research and Application, Medical University of Warsaw, Banacha 1B, 02-097 Warsaw, Poland
| | - Aleksandra Aksamit
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
| | - Katarzyna Zielniok
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
- Correspondence: (K.Z.); (A.B.)
| | - Monika Kniotek
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Beata Kaleta
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Aleksander Roszczyk
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Michal Zych
- Department of Clinical Immunology, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.K.); (B.K.); (A.R.); (M.Z.)
| | - Filip Dabrowski
- Department of Gynecology and Obstetrics, Medical University of Silesia, Medykow 14, 40-752 Katowice, Poland;
| | - Leszek Paczek
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Department of Bioinformatics, Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106 Warsaw, Poland
| | - Anna Burdzinska
- Department of Immunology, Transplantology and Internal Diseases, Medical University of Warsaw, Nowogrodzka 59, 02-006 Warsaw, Poland; (M.D.); (A.A.); (L.P.)
- Correspondence: (K.Z.); (A.B.)
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Sant'Ana AN, Araújo AB, Gonçalves FDC, Paz AH. Effects of living and metabolically inactive mesenchymal stromal cells and their derivatives on monocytes and macrophages. World J Stem Cells 2021; 13:1160-1176. [PMID: 34630856 PMCID: PMC8474715 DOI: 10.4252/wjsc.v13.i9.1160] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/23/2021] [Revised: 05/01/2021] [Accepted: 09/03/2021] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are multipotent and self-renewing stem cells that have great potential as cell therapy for autoimmune and inflammatory disorders, as well as for other clinical conditions, due to their immunoregulatory and regenerative properties. MSCs modulate the inflammatory milieu by releasing soluble factors and acting through cell-to-cell mechanisms. MSCs switch the classical inflammatory status of monocytes and macrophages towards a non-classical and anti-inflammatory phenotype. This is characterized by an increased secretion of anti-inflammatory cytokines, a decreased release of pro-inflammatory cytokines, and changes in the expression of cell membrane molecules and in metabolic pathways. The MSC modulation of monocyte and macrophage phenotypes seems to be critical for therapy effectiveness in several disease models, since when these cells are depleted, no immunoregulatory effects are observed. Here, we review the effects of living MSCs (metabolically active cells) and metabolically inactive MSCs (dead cells that lost metabolic activity by induced inactivation) and their derivatives (extracellular vesicles, soluble factors, extracts, and microparticles) on the profile of macrophages and monocytes and the implications for immunoregulatory and reparative processes. This review includes mechanisms of action exhibited in these different therapeutic approaches, which induce the anti-inflammatory properties of monocytes and macrophages. Finally, we overview several possibilities of therapeutic applications of these cells and their derivatives, with results regarding monocytes and macrophages in animal model studies and some clinical trials.
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Affiliation(s)
- Alexia Nedel Sant'Ana
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
| | - Anelise Bergmann Araújo
- Centro de Processamento Celular, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil.
| | | | - Ana Helena Paz
- Laboratório de Células Tecidos e Genes, Hospital de Clínicas de Porto Alegre, Porto Alegre 90035-903, RS, Brazil
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Chen Y, Shen H, Ding Y, Yu Y, Shao L, Shen Z. The application of umbilical cord-derived MSCs in cardiovascular diseases. J Cell Mol Med 2021; 25:8103-8114. [PMID: 34378345 PMCID: PMC8419197 DOI: 10.1111/jcmm.16830] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2021] [Revised: 06/29/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
Transplantation of stem cells is a promising, emerging treatment for cardiovascular diseases in the modern era. Mesenchymal stem cells (MSCs) derived from the umbilical cord are one of the most promising cell sources because of their capacity for differentiation into cardiomyocytes, endothelial cells and vascular smooth muscle cells in vitro/in vivo. In addition, umbilical cord‐derived MSCs (UC‐MSCs) secrete many effective molecules regulating apoptosis, fibrosis and neovascularization. Another important and specific characteristic of UC‐MSCs is their low immunogenicity and immunomodulatory properties. However, the application of UC‐MSCs still faces some challenges, such as low survivability and tissue retention in a harmful disease environment. Gene engineering and pharmacological studies have been implemented to overcome these difficulties. In this review, we summarize the differentiation ability, secretion function, immunoregulatory properties and preclinical/clinical studies of UC‐MSCs, highlighting the advantages of UC‐MSCs for the treatment of cardiovascular diseases.
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Affiliation(s)
- Yueqiu Chen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Han Shen
- Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Yinglong Ding
- Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - You Yu
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Lianbo Shao
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
| | - Zhenya Shen
- Institute for Cardiovascular Science, Soochow University, Suzhou, China.,Department of Cardiovascular Surgery of The First Affiliated Hospital, Soochow University, Suzhou, China
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Fields L, Ito T, Kobayashi K, Ichihara Y, Podaru MN, Hussain M, Yamashita K, Machado V, Lewis-McDougall F, Suzuki K. Epicardial placement of human MSC-loaded fibrin sealant films for heart failure: Preclinical efficacy and mechanistic data. Mol Ther 2021; 29:2554-2570. [PMID: 33887461 PMCID: PMC8353205 DOI: 10.1016/j.ymthe.2021.04.018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Revised: 02/28/2021] [Accepted: 04/15/2021] [Indexed: 12/31/2022] Open
Abstract
Mesenchymal stromal cell (MSC) transplantation has been investigated as an advanced treatment of heart failure; however, further improvement of the therapeutic efficacy and mechanistic understanding are needed. Our previous study has reported that epicardial placement of fibrin sealant films incorporating rat amniotic membrane-derived (AM)-MSCs (MSC-dressings) could address limitations of traditional transplantation methods. To progress this finding toward clinical translation, this current study aimed to examine the efficacy of MSC-dressings using human AM-MSCs (hAM-MSCs) and the underpinning mechanism for myocardial repair. Echocardiography demonstrated that cardiac function and structure were improved in a rat ischemic cardiomyopathy model after hAM-MSC-dressing therapy. hAM-MSCs survived well in the rat heart, enhanced myocardial expression of reparative genes, and attenuated adverse remodeling. Copy number analysis by qPCR revealed that upregulated reparative genes originated from endogenous rat cells rather than hAM-MSCs. These results suggest hAM-MSC-dressing therapy stimulates a secondary release of paracrine factors from endogenous cells improving myocardial repair ("secondary paracrine effect"), and cardiac M2-like macrophages were identified as a potential cell source of repair. We demonstrated hAM-MSCs increased M2-like macrophages through not only enhancing M2 polarization but also augmenting their proliferation and migration capabilities via PGE2, CCL2, and TGF-β1, resulting in enhanced cardiac function after injury.
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Affiliation(s)
- Laura Fields
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Tomoya Ito
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Yuki Ichihara
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mihai-Nicolae Podaru
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Mohsin Hussain
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Kizuku Yamashita
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Vanessa Machado
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Fiona Lewis-McDougall
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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Moradinasab S, Pourbagheri-Sigaroodi A, Zafari P, Ghaffari SH, Bashash D. Mesenchymal stromal/stem cells (MSCs) and MSC-derived extracellular vesicles in COVID-19-induced ARDS: Mechanisms of action, research progress, challenges, and opportunities. Int Immunopharmacol 2021; 97:107694. [PMID: 33932694 PMCID: PMC8079337 DOI: 10.1016/j.intimp.2021.107694] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2021] [Revised: 04/11/2021] [Accepted: 04/17/2021] [Indexed: 02/06/2023]
Abstract
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan city, Hubei province, China. Rapidly escalated into a worldwide pandemic, it has caused an unprecedented and devastating situation on the global public health and society economy. The severity of recent coronavirus disease, abbreviated to COVID-19, seems to be mostly associated with the patients' immune response. In this vein, mesenchymal stromal/stem cells (MSCs) have been suggested as a worth-considering option against COVID-19 as their therapeutic properties are mainly displayed in immunomodulation and anti-inflammatory effects. Indeed, administration of MSCs can attenuate cytokine storm and enhance alveolar fluid clearance, endothelial recovery, and anti-fibrotic regeneration. Despite advantages attributed to MSCs application in lung injuries, there are still several issues __foremost probability of malignant transformation and incidence of MSCs-related coagulopathy__ which should be resolved for the successful application of MSC therapy in COVID-19. In the present study, we review the historical evidence of successful use of MSCs and MSC-derived extracellular vesicles (EVs) in the treatment of acute respiratory distress syndrome (ARDS). We also take a look at MSCs mechanisms of action in the treatment of viral infections, and then through studying both the dark and bright sides of this approach, we provide a thorough discussion if MSC therapy might be a promising therapeutic approach in COVID-19 patients.
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Affiliation(s)
- Susan Moradinasab
- Iranian Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, Tehran, Iran
| | - Atieh Pourbagheri-Sigaroodi
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Parisa Zafari
- Department of Immunology, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
| | - Seyed H Ghaffari
- Hematology, Oncology and Stem Cell Transplantation Research Center, Shariati Hospital, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran
| | - Davood Bashash
- Department of Hematology and Blood Banking, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
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Huang Q, Cheng X, Luo C, Yang S, Li S, Wang B, Yuan X, Yang Y, Wen Y, Liu R, Tang L, Sun H. Placental chorionic plate-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating macrophage polarization via secreting TSG-6. Stem Cell Res Ther 2021; 12:337. [PMID: 34112260 PMCID: PMC8193892 DOI: 10.1186/s13287-021-02411-9] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2021] [Accepted: 05/24/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Mesenchymal stem cells (MSCs) hold promising potential to treat systemic inflammatory diseases including severe acute pancreatitis (SAP). In our previous study, placental chorionic plate-derived MSCs (CP-MSCs) were found to possess superior immunoregulatory capability. However, the therapeutic efficacy of CP-MSCs on SAP and their underlying mechanism remain unclear. METHODS The survival and colonization of exogenous CP-MSCs were observed by bioluminescence imaging and CM-Dil labeling in rodent animal models of SAP. The therapeutic efficacy of CP-MSCs on SAP rats was evaluated by pathology scores, the levels of pancreatitis biomarkers as well as the levels of inflammatory factors in the pancreas and serum. The potential protective mechanism of CP-MSCs in SAP rats was explored by selectively depleting M1 or M2 phenotype macrophages and knocking down the expression of TSG-6. RESULTS Exogenous CP-MSCs could survive and colonize in the injured tissue of SAP such as the lung, pancreas, intestine, and liver. Meanwhile, we found that CP-MSCs alleviated pancreatic injury and systemic inflammation by inducing macrophages to polarize from M1 to M2 in SAP rats. Furthermore, our data suggested that CP-MSCs induced M2 polarization of macrophages by secreting TSG-6, and TSG-6 played a vital role in alleviating pancreatic injury and systemic inflammation in SAP rats. Notably, we found that a high inflammation environment could stimulate CP-MSCs to secrete TSG-6. CONCLUSION Exogenous CP-MSCs tended to colonize in the injured tissue and reduced pancreatic injury and systemic inflammation in SAP rats through inducing M2 polarization of macrophages by secreting TSG-6. Our study provides a new treatment strategy for SAP and initially explains the potential protective mechanism of CP-MSCs on SAP rats.
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Affiliation(s)
- Qilin Huang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China.,Tianjin Medical University, Tianjin, 300070, China
| | - Xiumei Cheng
- XinDu Hospital of Traditional Chinese Medicine & Chengdu 2nd Hospital of Traditional Chinese Medicine, Chengdu, 610500, China
| | - Chen Luo
- Division of Hepatobiliary Pancreatic Surgery, Panzhihua Central Hospital, Sichuan Province, Panzhihua, 617017, China
| | - Shuxu Yang
- Tianjin Medical University, Tianjin, 300070, China
| | - Shuai Li
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Bing Wang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Xiaohui Yuan
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Yi Yang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Yi Wen
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Ruohong Liu
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China
| | - Lijun Tang
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China.
| | - Hongyu Sun
- Department of General Surgery & Pancreatic Injury and Repair Key Laboratory of Sichuan Province, The General Hospital of Western Theater Command, Chengdu, 610083, China. .,Laboratory of Basic Medicine, The General Hospital of Western Theater Command, Chengdu, 610031, China.
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40
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Germena G, Hinkel R. iPSCs and Exosomes: Partners in Crime Fighting Cardiovascular Diseases. J Pers Med 2021; 11:jpm11060529. [PMID: 34207562 PMCID: PMC8230331 DOI: 10.3390/jpm11060529] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2021] [Revised: 05/31/2021] [Accepted: 06/07/2021] [Indexed: 12/17/2022] Open
Abstract
Cardiovascular diseases are the leading cause of mortality worldwide. Understanding the mechanisms at the basis of these diseases is necessary in order to generate therapeutic approaches. Recently, cardiac tissue engineering and induced pluripotent stem cell (iPSC) reprogramming has led to a skyrocketing number of publications describing cardiovascular regeneration as a promising option for cardiovascular disease treatment. Generation of artificial tissue and organoids derived from induced pluripotent stem cells is in the pipeline for regenerative medicine. The present review summarizes the multiple approaches of heart regeneration with a special focus on iPSC application. In particular, we describe the strength of iPSCs as a tool to study the molecular mechanisms driving cardiovascular pathologies, as well as their potential in drug discovery. Moreover, we will describe some insights into novel discoveries of how stem-cell-secreted biomolecules, such as exosomes, could affect cardiac regeneration, and how the fine tuning of the immune system could be a revolutionary tool in the modulation of heart regeneration.
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Affiliation(s)
- Giulia Germena
- Laboratory Animal Science Unit, Leibniz-Institut für Primatenforschung, Deutsches Primatenzentrum GmbH, Kellnerweg 4, 37077 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, 37077 Göttingen, Germany
- Correspondence: (G.G.); (R.H.)
| | - Rabea Hinkel
- Laboratory Animal Science Unit, Leibniz-Institut für Primatenforschung, Deutsches Primatenzentrum GmbH, Kellnerweg 4, 37077 Göttingen, Germany
- DZHK (German Center for Cardiovascular Research), Partner Site Göttingen, 37077 Göttingen, Germany
- Stiftung Tierärztliche Hochschule Hannover, University of Veterinary Medicine, 30559 Hannover, Germany
- Correspondence: (G.G.); (R.H.)
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41
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Raposo L, Lourenço AP, Nascimento DS, Cerqueira R, Cardim N, Leite-Moreira A. Human umbilical cord tissue-derived mesenchymal stromal cells as adjuvant therapy for myocardial infarction: a review of current evidence focusing on pre-clinical large animal models and early human trials. Cytotherapy 2021; 23:974-979. [PMID: 34112613 DOI: 10.1016/j.jcyt.2021.05.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 04/25/2021] [Accepted: 05/06/2021] [Indexed: 12/28/2022]
Abstract
Although biologically appealing, the concept of tissue regeneration underlying first- and second-generation cell therapies has failed to translate into consistent results in clinical trials. Several types of cells from different origins have been tested in pre-clinical models and in patients with acute myocardial infarction (AMI). Mesenchymal stromal cells (MSCs) have gained attention because of their potential for immune modulation and ability to promote endogenous tissue repair, mainly through their secretome. MSCs can be easily obtained from several human tissues, the umbilical cord being the most abundant source, and further expanded in culture, making them attractive as an allogeneic "of-the-shelf" cell product, suitable for the AMI setting. The available evidence concerning umbilical cord-derived MSCs in AMI is reviewed, focusing on large animal pre-clinical studies and early human trials. Molecular and cellular mechanisms as well as current limitations and possible translational solutions are also discussed.
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Affiliation(s)
- Luís Raposo
- Cardiology Department, Santa Cruz Hospital, West Lisbon Hospital Center, Lisbon, Portugal; Hospital da Luz Lisboa, Luz Saúde, Lisbon, Portugal; Nova Medical School, Lisbon, Portugal.
| | - André P Lourenço
- Department of Cardiac Surgery, University Hospital Centre São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Diana S Nascimento
- Institute for Research and Innovation in Health, University of Porto, Portugal; Instituto de Ciências Biomédicas Abel Salazar, University of Porto, Portugal; Instituto Nacional de Engenharia Biomédica, University of Porto, Portugal
| | - Rui Cerqueira
- Department of Cardiac Surgery, University Hospital Centre São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
| | - Nuno Cardim
- Hospital da Luz Lisboa, Luz Saúde, Lisbon, Portugal; Nova Medical School, Lisbon, Portugal
| | - Adelino Leite-Moreira
- Department of Cardiac Surgery, University Hospital Centre São João, Porto, Portugal; Department of Surgery and Physiology, Faculty of Medicine, University of Porto, Porto, Portugal
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42
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Macrophages and Stem Cells-Two to Tango for Tissue Repair? Biomolecules 2021; 11:biom11050697. [PMID: 34066618 PMCID: PMC8148606 DOI: 10.3390/biom11050697] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2021] [Revised: 04/26/2021] [Accepted: 05/04/2021] [Indexed: 12/25/2022] Open
Abstract
Macrophages (MCs) are present in all tissues, not only supporting homeostasis, but also playing an important role in organogenesis, post-injury regeneration, and diseases. They are a heterogeneous cell population due to their origin, tissue specificity, and polarization in response to aggression factors, depending on environmental cues. Thus, as pro-inflammatory M1 phagocytic MCs, they contribute to tissue damage and even fibrosis, but the anti-inflammatory M2 phenotype participates in repairing processes and wound healing through a molecular interplay with most cells in adult stem cell niches. In this review, we emphasize MC phenotypic heterogeneity in health and disease, highlighting their systemic and systematic contribution to tissue homeostasis and repair. Unraveling the intervention of both resident and migrated MCs on the behavior of stem cells and the regulation of the stem cell niche is crucial for opening new perspectives for novel therapeutic strategies in different diseases.
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Caldwell AS, Rao VV, Golden AC, Bell DJ, Grim JC, Anseth KS. Mesenchymal stem cell-inspired microgel scaffolds to control macrophage polarization. Bioeng Transl Med 2021; 6:e10217. [PMID: 34027099 PMCID: PMC8126823 DOI: 10.1002/btm2.10217] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 02/25/2021] [Accepted: 03/01/2021] [Indexed: 12/12/2022] Open
Abstract
There is a desire in regenerative medicine to create biofunctional materials that can control and direct cell function in a precise manner. One particular stem cell of interest, human mesenchymal stem cells (hMSCs), can function as regulators of the immunogenic response and aid in tissue regeneration and wound repair. Here, a porous hydrogel scaffold assembled from microgel subunits was used to recapitulate part of this immunomodulatory behavior. The scaffolds were used to culture a macrophage cell line, while cytokines were delivered exogenously to polarize the macrophages to either a pro-inflammatory (M1) or alternatively activated (M2a) phenotypes. Using a cytokine array, interleukin 10 (IL-10) was identified as one key anti-inflammatory factor secreted by hMSCs in pro-inflammatory conditions; it was elevated (125 ± 25 pg/ml) in pro-inflammatory conditions compared to standard medium (6 ± 10 pg/ml). The ability of hMSC laden scaffolds to reverse the M1 phenotype was then examined, even in the presence of exogenous pro-inflammatory cytokines. Co-culture of M1 and M2 macrophages with hMSCs reduced the secretion of TNFα, a pro-inflammatory cytokine even in the presence of pro-inflammatory stimulatory factors. Next, IL-10 was supplemented in the medium or tethered directly to the microgel subunits; both methods limited the secretion of pro-inflammatory cytokines of encapsulated macrophages even in pro-inflammatory conditions. Cumulatively, these results reveal the potential of biofunctional microgel-based scaffolds as acellular therapies to present anti-inflammatory cytokines and control the immunogenic cascade.
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Affiliation(s)
- Alexander S. Caldwell
- Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderColoradoUSA
- BioFrontiers Institute, University of ColoradoBoulderColoradoUSA
| | - Varsha V. Rao
- Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderColoradoUSA
- BioFrontiers Institute, University of ColoradoBoulderColoradoUSA
| | - Alyxandra C. Golden
- Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderColoradoUSA
| | - Daniel J. Bell
- Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderColoradoUSA
- BioFrontiers Institute, University of ColoradoBoulderColoradoUSA
| | - Joseph C. Grim
- Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderColoradoUSA
- BioFrontiers Institute, University of ColoradoBoulderColoradoUSA
| | - Kristi S. Anseth
- Department of Chemical and Biological EngineeringUniversity of ColoradoBoulderColoradoUSA
- BioFrontiers Institute, University of ColoradoBoulderColoradoUSA
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Interleukin-34 levels are increased in acute myocardial infarction and associated with major adverse cardiovascular events. Coron Artery Dis 2021; 31:61-63. [PMID: 33899760 DOI: 10.1097/mca.0000000000001046] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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Li Y, Dong M, Wang Q, Kumar S, Zhang R, Cheng W, Xiang J, Wang G, Ouyang K, Zhou R, Xie Y, Lu Y, Yi J, Duan H, Liu J. HIMF deletion ameliorates acute myocardial ischemic injury by promoting macrophage transformation to reparative subtype. Basic Res Cardiol 2021; 116:30. [PMID: 33893593 PMCID: PMC8064941 DOI: 10.1007/s00395-021-00867-7] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 03/31/2021] [Indexed: 12/12/2022]
Abstract
Appropriately manipulating macrophage M1/M2 phenotypic transition is a promising therapeutic strategy for tissue repair after myocardial infarction (MI). Here we showed that gene ablation of hypoxia-induced mitogenic factor (HIMF) in mice (Himf−/− and HIMFflox/flox;Lyz2-Cre) attenuated M1 macrophage-dominated inflammatory response and promoted M2 macrophage accumulation in infarcted hearts. This in turn reduced myocardial infarct size and improved cardiac function after MI. Correspondingly, expression of HIMF in macrophages induced expression of pro-inflammatory cytokines; the culturing medium of HIMF-overexpressing macrophages impaired the cardiac fibroblast viability and function. Furthermore, macrophage HIMF was found to up-regulate C/EBP-homologous protein (CHOP) expression, which exaggerated the release of pro-inflammatory cytokines via activating signal transducer of activator of transcription 1 (STAT1) and 3 (STAT3) signaling. Together these data suggested that HIMF promotes M1-type and prohibits M2-type macrophage polarization by activating the CHOP–STAT1/STAT3 signaling pathway to negatively regulate myocardial repair. HIMF might thus constitute a novel target to treat MI.
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Affiliation(s)
- Yanjiao Li
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Min Dong
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Qing Wang
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Santosh Kumar
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Rui Zhang
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Wanwen Cheng
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Jiaqing Xiang
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Gang Wang
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Kunfu Ouyang
- Drug Discovery Center, State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School, Peking University, Shenzhen, 51055, China
| | - Ruxing Zhou
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Yaohong Xie
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Yishen Lu
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Jing Yi
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Haixia Duan
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China.,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China
| | - Jie Liu
- Guangdong Key Laboratory of Genome Stability and Human Disease Prevention, Department of Pathophysiology, Shenzhen University Health Science Center, Shenzhen, 518060, China. .,Guangdong Key Laboratory of Regional Immunity and Diseases, Department of Pathology, Shenzhen University Health Science Center, Shenzhen, 518060, China.
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Bolli R, Solankhi M, Tang XL, Kahlon A. Cell Therapy in Patients with Heart Failure: A Comprehensive Review and Emerging Concepts. Cardiovasc Res 2021; 118:951-976. [PMID: 33871588 PMCID: PMC8930075 DOI: 10.1093/cvr/cvab135] [Citation(s) in RCA: 67] [Impact Index Per Article: 16.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2020] [Accepted: 04/15/2021] [Indexed: 12/16/2022] Open
Abstract
This review summarizes the results of clinical trials of cell therapy in patients with heart failure (HF). In contrast to acute myocardial infarction (where results have been consistently negative for more than a decade), in the setting of HF the results of Phase I–II trials are encouraging, both in ischaemic and non-ischaemic cardiomyopathy. Several well-designed Phase II studies have met their primary endpoint and demonstrated an efficacy signal, which is remarkable considering that only one dose of cells was used. That an efficacy signal was seen 6–12 months after a single treatment provides a rationale for larger, rigorous trials. Importantly, no safety concerns have emerged. Amongst the various cell types tested, mesenchymal stromal cells derived from bone marrow (BM), umbilical cord, or adipose tissue show the greatest promise. In contrast, embryonic stem cells are not likely to become a clinical therapy. Unfractionated BM cells and cardiosphere-derived cells have been abandoned. The cell products used for HF will most likely be allogeneic. New approaches, such as repeated cell treatment and intravenous delivery, may revolutionize the field. As is the case for most new therapies, the development of cell therapies for HF has been slow, plagued by multifarious problems, and punctuated by many setbacks; at present, the utility of cell therapy in HF remains to be determined. What the field needs is rigorous, well-designed Phase III trials. The most important things to move forward are to keep an open mind, avoid preconceived notions, and let ourselves be guided by the evidence.
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Affiliation(s)
- Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Mitesh Solankhi
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Xiang-Liang Tang
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
| | - Arunpreet Kahlon
- Institute of Molecular Cardiology, University of Louisville, Louisville, KY 40292
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New Insights and Novel Therapeutic Potentials for Macrophages in Myocardial Infarction. Inflammation 2021; 44:1696-1712. [PMID: 33866463 PMCID: PMC8460536 DOI: 10.1007/s10753-021-01467-2] [Citation(s) in RCA: 46] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/09/2021] [Accepted: 04/05/2021] [Indexed: 12/19/2022]
Abstract
Cardiovascular disease (CVD) has long been the leading cause of death worldwide, and myocardial infarction (MI) accounts for the greatest proportion of CVD. Recent research has revealed that inflammation plays a major role in the pathogenesis of CVD and other manifestations of atherosclerosis. Overwhelming evidence supports the view that macrophages, as the basic cell component of the innate immune system, play a pivotal role in atherosclerosis initiation and progression. Limited but indispensable resident macrophages have been detected in the healthy heart; however, the number of cardiac macrophages significantly increases during cardiac injury. In the early period of initial cardiac damage (e.g., MI), numerous classically activated macrophages (M1) originating from the bone marrow and spleen are rapidly recruited to damaged sites, where they are responsible for cardiac remodeling. After the inflammatory stage, the macrophages shift toward an alternatively activated phenotype (M2) that promotes cardiac repair. In addition, extensive studies have shown the therapeutic potential of macrophages as targets, especially for emerging nanoparticle-mediated drug delivery systems. In the present review, we focused on the role of macrophages in the development and progression of MI, factors regulating macrophage activation and function, and the therapeutic potential of macrophages in MI.
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Hasgur S, Desbourdes L, Relation T, Overholt KM, Stanek JR, Guess AJ, Yu M, Patel P, Roback L, Dominici M, Otsuru S, Horwitz EM. Splenic macrophage phagocytosis of intravenously infused mesenchymal stromal cells attenuates tumor localization. Cytotherapy 2021; 23:411-422. [PMID: 33781710 DOI: 10.1016/j.jcyt.2020.04.102] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 04/17/2020] [Accepted: 04/28/2020] [Indexed: 12/13/2022]
Abstract
Mesenchymal stromal cells (MSCs) possess remarkable tumor tropism, making them ideal vehicles to deliver tumor-targeted therapeutic agents; however, their value in clinical medicine has yet to be realized. A barrier to clinical utilization is that only a small fraction of infused MSCs ultimately localize to the tumor. In an effort to overcome this obstacle, we sought to enhance MSC trafficking by focusing on the factors that govern MSC arrival within the tumor microenvironment. Our findings show that MSC chemoattraction is only present in select tumors, including osteosarcoma, and that the chemotactic potency among similar tumors varies substantially. Using an osteosarcoma xenograft model, we show that human MSCs traffic to the tumor within several hours of infusion. After arrival, MSCs are observed to localize in clusters near blood vessels and MSC-associated bioluminescence signal intensity is increased, suggesting that the seeded cells expand after engraftment. However, our studies reveal that a significant portion of MSCs are eliminated en route by splenic macrophage phagocytosis, effectively limiting the number of cells available for tumor engraftment. To increase MSC survival, we transiently depleted macrophages with liposomal clodronate, which resulted in increased tumor localization without substantial reduction in tumor-associated macrophages. Our data suggest that transient macrophage depletion will significantly increase the number of MSCs in the spleen and thus improve MSC localization within a tumor, theoretically increasing the effective dose of an anti-cancer agent. This strategy may subsequently improve the clinical efficacy of MSCs as vehicles for the tumor-directed delivery of therapeutic agents.
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Affiliation(s)
- Suheyla Hasgur
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Laura Desbourdes
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Theresa Relation
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Kathleen M Overholt
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Joseph R Stanek
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Adam J Guess
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Minjun Yu
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Pratik Patel
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Linda Roback
- Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA
| | - Massimo Dominici
- Department of Medical and Surgical Sciences of Children and Adults, University of Modena and Reggio Emilia, Modena, Italy
| | - Satoru Otsuru
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA
| | - Edwin M Horwitz
- Center for Childhood Cancer and Blood Diseases, The Research Institute at Nationwide Children's Hospital, Columbus, Ohio, USA; Aflac Cancer & Blood Disorders Center, Children's Healthcare of Atlanta, Emory University School of Medicine, Atlanta, Georgia, USA.
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Cardiac Cell Therapy: Insights into the Mechanisms of Tissue Repair. Int J Mol Sci 2021; 22:ijms22031201. [PMID: 33530466 PMCID: PMC7865339 DOI: 10.3390/ijms22031201] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 01/20/2021] [Accepted: 01/22/2021] [Indexed: 12/12/2022] Open
Abstract
Stem cell-based cardiac therapies have been extensively studied in recent years. However, the efficacy of cell delivery, engraftment, and differentiation post-transplant remain continuous challenges and represent opportunities to further refine our current strategies. Despite limited long-term cardiac retention, stem cell treatment leads to sustained cardiac benefit following myocardial infarction (MI). This review summarizes the current knowledge on stem cell based cardiac immunomodulation by highlighting the cellular and molecular mechanisms of different immune responses to mesenchymal stem cells (MSCs) and their secretory factors. This review also addresses the clinical evidence in the field.
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Rodriguez HC, Gupta M, Cavazos-Escobar E, El-Amin SF, Gupta A. Umbilical cord: an allogenic tissue for potential treatment of COVID-19. Hum Cell 2021; 34:1-13. [PMID: 33033884 PMCID: PMC7544522 DOI: 10.1007/s13577-020-00444-5] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2020] [Accepted: 09/30/2020] [Indexed: 12/18/2022]
Abstract
The COVID-19 pandemic has placed an unprecedented burden on health care systems and economies around the globe. Clinical evidences demonstrate that SARS-CoV-2 infection produces detrimental levels of pro-inflammatory cytokines and chemokines that can lead to acute respiratory distress syndrome (ARDS) and significant systemic organ damage. Currently, there is no definitive therapy for COVID-19 or associated complications, and with the hope of a safe and effective vaccine in the distant future, the search for an answer is paramount. Mesenchymal stem cells (MSCs) provide a viable option due to their immunomodulatory effects and tissue repair and regeneration abilities. Studies have demonstrated that compassionate use of MSCs can reduce symptoms associated with SARS-CoV-2 infection, eliminate fluid buildup, and act as a regenerative technique for alveolar damage; all in a safe and effective way. With multiple autologous sources available for MSCs, each with their own respective limitations, allogenic umbilical cord (UC) and/or UC-derived Wharton's jelly (WJ) seem to be best positioned source to harvest MSCs to treat COVID-19 and associated symptoms. As an allogenic source, UC is readily available, easily obtainable, and is rich in immunomodulatory and regenerative factors. In this manuscript, we reviewed the current evidences and explored the potential therapeutic use of allogenic UC and/or WJ-derived MSCs for the treatment of COVID-19. Although, preliminary preclinical and clinical studies indicate that their use is safe and potentially effective, more multi-center, randomized, controlled trials are needed to adequately assess the safety and efficacy of UC and/or WJ-derived MSCs for the treatment of COVID-19.
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Affiliation(s)
- Hugo C. Rodriguez
- Future Biologics, 1110 Ballpark Ln Apt 5109, Lawrenceville, GA 30043 USA
- Future Physicians of South Texas, San Antonio, TX USA
- School of Osteopathic Medicine, University of the Incarnate Word, San Antonio, TX USA
- South Texas Orthopaedic Research Institute, Laredo, TX USA
| | - Manu Gupta
- Future Biologics, 1110 Ballpark Ln Apt 5109, Lawrenceville, GA 30043 USA
| | - Emilio Cavazos-Escobar
- Future Physicians of South Texas, San Antonio, TX USA
- University of Texas Medical Branch at Galveston, Galveston, TX USA
| | - Saadiq F. El-Amin
- El-Amin Orthopaedic and Sports Medicine Institute, Lawrenceville, GA USA
- BioIntegrate, Lawrenceville, GA USA
| | - Ashim Gupta
- Future Biologics, 1110 Ballpark Ln Apt 5109, Lawrenceville, GA 30043 USA
- South Texas Orthopaedic Research Institute, Laredo, TX USA
- BioIntegrate, Lawrenceville, GA USA
- Veterans in Pain, Los Angeles, CA USA
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