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Narvekar S, Baliga SD, Angadi PV. Dental pulp stem cells as a novel antifibrotic therapy for oral submucous fibrosis: An in vitro study. J Oral Biol Craniofac Res 2025; 15:383-389. [PMID: 40034371 PMCID: PMC11872489 DOI: 10.1016/j.jobcr.2025.02.002] [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: 12/26/2024] [Revised: 02/02/2025] [Accepted: 02/04/2025] [Indexed: 03/05/2025] Open
Abstract
Background Oral submucous fibrosis (OSMF) is a chronic, potentially malignant disorder associated with areca nut consumption. It is characterized by progressive fibrosis, trismus, and a significant risk of malignancy, with limited treatment options primarily offering symptomatic relief. Dental pulp stem cells (DPSCs), a type of mesenchymal stem cells (MSCs), have shown potential for modulating fibrotic conditions through their immunomodulatory and regenerative properties. This study evaluates the antifibrotic potential of DPSCs on OSMF fibroblasts in an in vitro model. Methods DPSCs were isolated from healthy permanent teeth and characterized using flow cytometry for MSC markers (CD73, CD90, CD44, CD105). Fibroblasts were cultured from OSMF biopsy samples and validated through magnetic sorting and morphological analysis. The antifibrotic effects of DPSCs on fibroblasts were evaluated using assays for collagen gel contraction, proliferation, TGF-β1 secretion, and morphological changes. Data were analyzed for statistical significance using appropriate tests. Results The mean collagen gel size decreased from 3.235 mm (95 % CI: 1.65-4.82 mm) in the control group to 1.00 mm (95 % CI: -0.27 - 2.27 mm) in the DPSC-treated group. Fibroblast viability declined significantly over 72 h (p < 0.05). TGF-β1 secretion was markedly lower in DPSC-treated fibroblasts (339.38 pg/mL vs 637.61 pg/mL, p = 0.000393, Cohen's d = 19.15). Conclusion DPSCs exhibit strong antifibrotic properties by inhibiting collagen contraction, suppressing fibroblast proliferation, and reducing TGF-β1 secretion. These findings suggest DPSCs as a promising cell-based therapy for OSMF. Further in vivo studies are warranted for clinical translation. Trial registration number Not applicable.
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Affiliation(s)
- Snehalata Narvekar
- Department of Oral and Maxillofacial Surgery,KLE V K Institute of Dental Sciences, K LE Academy of Higher Education and Research, Belagavi, India
| | - Shridhar D. Baliga
- Department of Oral and Maxillofacial Surgery, KLE V K Institute of Dental Sciences, KLE Academy of Higher Education and Research, Belagavi, India
| | - Punnya V Angadi
- Department of Oral and Maxillofacial Pathology and Microbiology, KLE V K Institute of Dental Sciences, KLE Academy of Higher Education and Research, Belagavi, India
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El Assaad N, Chebly A, Salame R, Achkar R, Bou Atme N, Akouch K, Rafoul P, Hanna C, Abou Zeid S, Ghosn M, Khalil C. Anti-aging based on stem cell therapy: A scoping review. World J Exp Med 2024; 14:97233. [PMID: 39312703 PMCID: PMC11372738 DOI: 10.5493/wjem.v14.i3.97233] [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: 05/26/2024] [Revised: 07/04/2024] [Accepted: 07/18/2024] [Indexed: 08/29/2024] Open
Abstract
Stem cells are present in the tissues and organs and remain in a quiescent and undifferentiated state until it is physiologically necessary to produce new descendant cells. Due to their multipotency property, mesenchymal stem cells have attracted considerable attention worldwide due to their immunomodulation and therapeutic function in tissue regeneration. Stem cells secrete components such as paracrine factors, extracellular vesicles, and exosomes which have been shown to have anti-inflammatory, anti-aging, reconstruction and wound healing potentials in many in vitro and in vivo models. The pluripotency and immunomodulatory features of stem cells could potentially be an effective tool in cell therapy and tissue repair. Aging affects the capacity for self-renewal and differentiation of stem cells, decreasing the potential for regeneration and the loss of optimal functions in organisms over time. Current progress in the field of cellular therapy and regenerative medicine has facilitated the evolution of particular guidelines and quality control approaches, which eventually lead to clinical trials. Cell therapy could potentially be one of the most promising therapies to control aging due to the fact that single stem cell transplantation can regenerate or substitute the injured tissue. To understand the involvement of stem cells not only in tissue maintenance and disease but also in the control of aging it is important to know and identify their properties, functions, and regulation in vivo, which are addressed in this review.
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Affiliation(s)
- Nassar El Assaad
- Faculty of Medicine, Saint Joseph University, Beirut 961, Lebanon
| | - Alain Chebly
- Centre Jacques Loiselet for Medical Genetics and Genomics (CGGM), Faculty of Medicine, Saint Joseph University, Beirut 961, Lebanon
- Higher Institute of Public Health, Saint Joseph University, Beirut 961, Lebanon
| | - Rawad Salame
- Stem Cell Therapy Lab, Reviva Regenerative Medicine Center, Beirut 961, Lebanon
| | - Robert Achkar
- Poz Pozan University of Medical Sciences, Pozan 034, Poland
| | - Nour Bou Atme
- Faculty of Medicine, Saint Joseph University, Beirut 961, Lebanon
| | - Khalil Akouch
- Stem Cell Therapy Lab, Reviva Regenerative Medicine Center, Beirut 961, Lebanon
| | - Paul Rafoul
- Department of Epidemiology and Biostatistics, Faculty of Public Health, Lebanese University, Beirut 961, Lebanon
| | - Colette Hanna
- School of Medicine, Lebanese American University, Beirut 961, Lebanon
| | - Samer Abou Zeid
- Faculty of Medicine, Saint Joseph University, Beirut 961, Lebanon
| | - Marwan Ghosn
- Faculty of Medicine, Saint Joseph University, Beirut 961, Lebanon
| | - Charbel Khalil
- Stem Cell Therapy Lab, Reviva Regenerative Medicine Center, Beirut 961, Lebanon
- School of Medicine, Lebanese American University, Beirut 961, Lebanon
- Bone Marrow Transplant Unit, Burjeel Medical City, Abu Dhabi 999041, United Arab Emirates
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Almadori A, Butler PEM. Scarring and Skin Fibrosis Reversal with Regenerative Surgery and Stem Cell Therapy. Cells 2024; 13:443. [PMID: 38474408 PMCID: PMC10930731 DOI: 10.3390/cells13050443] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2024] [Revised: 02/22/2024] [Accepted: 02/27/2024] [Indexed: 03/14/2024] Open
Abstract
Skin scarring and fibrosis affect millions of people worldwide, representing a serious clinical problem causing physical and psychological challenges for patients. Stem cell therapy and regenerative surgery represent a new area of treatment focused on promoting the body's natural ability to repair damaged tissue. Adipose-derived stem cells (ASCs) represent an optimal choice for practical regenerative medicine due to their abundance, autologous tissue origin, non-immunogenicity, and ease of access with minimal morbidity for patients. This review of the literature explores the current body of evidence around the use of ASCs-based regenerative strategies for the treatment of scarring and skin fibrosis, exploring the different surgical approaches and their application in multiple fibrotic skin conditions. Human, animal, and in vitro studies demonstrate that ASCs present potentialities in modifying scar tissue and fibrosis by suppressing extracellular matrix (ECM) synthesis and promoting the degradation of their constituents. Through softening skin fibrosis, function and overall quality of life may be considerably enhanced in different patient cohorts presenting with scar-related symptoms. The use of stem cell therapies for skin scar repair and regeneration represents a paradigm shift, offering potential alternative therapeutic avenues for fibrosis, a condition that currently lacks a cure.
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Affiliation(s)
- Aurora Almadori
- Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College of London, London NW3 2QG, UK;
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London NW3 2QG, UK
- The Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital Campus, University College of London, London NW3 2QG, UK
| | - Peter EM Butler
- Centre for Nanotechnology and Regenerative Medicine, Division of Surgery & Interventional Science, University College of London, London NW3 2QG, UK;
- Department of Plastic Surgery, Royal Free London NHS Foundation Trust Hospital, London NW3 2QG, UK
- The Charles Wolfson Centre for Reconstructive Surgery, Royal Free Hospital Campus, University College of London, London NW3 2QG, UK
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Elzainy A, El Sadik A, Altowayan WM. Comparison between the Regenerative and Therapeutic Impacts of Bone Marrow Mesenchymal Stem Cells and Adipose Mesenchymal Stem Cells Pre-Treated with Melatonin on Liver Fibrosis. Biomolecules 2024; 14:297. [PMID: 38540717 PMCID: PMC10968153 DOI: 10.3390/biom14030297] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2024] [Revised: 02/14/2024] [Accepted: 02/28/2024] [Indexed: 01/06/2025] Open
Abstract
BACKGROUND The distinctive feature of liver fibrosis is the progressive replacement of healthy hepatic cells by the extracellular matrix protein, which is abundant in collagen I and III, with impaired matrix remodeling. The activation of myofibroblastic cells enhances the fibrogenic response of complex interactions of hepatic stellate cells, fibroblasts, and inflammatory cells to produce the excessive deposition of the extracellular protein matrix. This process is activated by multiple fibrogenic mediators and cytokines, such as TNF-α and IL-1β, accompanied with a decrease in the anti-fibrogenic factor NF-κβ. Mesenchymal stem cells (MSCs) represent a promising therapy for liver fibrosis, allowing for a more advanced regenerative influence when cultured with extrinsic or intrinsic proliferative factors, cytokines, antioxidants, growth factors, and hormones such as melatonin (MT). However, previous studies showed conflicting findings concerning the therapeutic effects of adipose (AD) and bone marrow (BM) MSCs; therefore, the present work aimed to conduct a comparative and comprehensive study investigating the impact of MT pre-treatment on the immunomodulatory, anti-inflammatory, and anti-apoptotic effects of AD- and BM-MSCs and to critically analyze whether MT-pre-treated AD-MSCs and BM-MSCs reveal equal or different therapeutic and regenerative potentials in a CCl4-injured liver experimental rat model. MATERIALS AND METHODS Six groups of experimental rats were used, with ten rats in each group: group I (control group), group II (CCl4-treated group), group III (CCl4- and BM-MSC-treated group), group IV (CCl4 and MT-pre-treated BM-MSC group), group V (CCl4- and AD-MSC-treated group), and group VI (CCl4 and MT-pre-treated AD-MSC group). Liver function tests and the gene expression of inflammatory, fibrogenic, apoptotic, and proliferative factors were analyzed. Histological and immunohistochemical changes were assessed. RESULTS The present study compared the ability of AD- and BM-MSCs, with and without MT pre-treatment, to reduce hepatic fibrosis. Both types of MSCs improved hepatocyte function by reducing the serum levels of ALT, aspartate aminotransferase (AST), alkaline phosphatase (AKP), and total bilirubin (TBIL). In addition, the changes in the hepatocellular architecture, including the hepatocytes, liver sinusoids, central veins, portal veins, biliary ducts, and hepatic arteries, showed a decrease in hepatocyte injury and cholestasis with a reduction in inflammation, apoptosis, and necrosis of the hepatic cells, together with an inhibition of liver tissue fibrosis. These results were augmented by an analysis of the expression of the pro-inflammatory cytokines TNFα and IL-1β, the anti-fibrogenic factor NF-κβ, the apoptotic factor caspase-3, and the proliferative indicators antigen Ki-67 and proliferating cell nuclear antigen (PCNA). These findings were found to be statistically significant, with the restoration of normal parameters in the rats that received AD-MSCs pre-treated with MT, denoting optimal regenerative and therapeutic effects. CONCLUSIONS AD-MSCs pre-treated with MT are the preferred choice in improving hepatic fibrosis and promoting the therapeutic and regenerative ability of liver tissue. They represent a very significant tool for future stem cell use in the tissue regeneration strategy for the treatment of liver diseases.
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Affiliation(s)
- Ahmed Elzainy
- Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia; (A.E.); (A.E.S.)
- Department of Anatomy and Embryology, College of Medicine, Cairo University, Cairo 11956, Egypt
| | - Abir El Sadik
- Department of Anatomy and Histology, College of Medicine, Qassim University, Buraydah 51452, Saudi Arabia; (A.E.); (A.E.S.)
- Department of Anatomy and Embryology, College of Medicine, Cairo University, Cairo 11956, Egypt
| | - Waleed Mohammad Altowayan
- Department of Pharmacy Practice, College of Pharmacy, Qassim University, Buraydah 51452, Saudi Arabia
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Goligorsky MS. Permissive role of vascular endothelium in fibrosis: focus on the kidney. Am J Physiol Cell Physiol 2024; 326:C712-C723. [PMID: 38223932 PMCID: PMC11193458 DOI: 10.1152/ajpcell.00526.2023] [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: 10/11/2023] [Revised: 01/09/2024] [Accepted: 01/09/2024] [Indexed: 01/16/2024]
Abstract
Fibrosis, the morphologic end-result of a plethora of chronic conditions and the scorch for organ function, has been thoroughly investigated. One aspect of its development and progression, namely the permissive role of vascular endothelium, has been overshadowed by studies into (myo)fibroblasts and TGF-β; thus, it is the subject of the present review. It has been established that tensile forces of the extracellular matrix acting on cells are a prerequisite for mechanochemical coupling, leading to liberation of TGF-β and formation of myofibroblasts. Increased tensile forces are prompted by elevated vascular permeability in response to diverse stressors, resulting in the exudation of fibronectin, fibrinogen/fibrin, and other proteins, all stiffening the extracellular matrix. These processes lead to the development of endothelial cells dysfunction, endothelial-to-mesenchymal transition, premature senescence of endothelial cells, perturbation of blood flow, and gradual obliteration of microvasculature, leaving behind "string" vessels. The resulting microvascular rarefaction is not only a constant companion of fibrosis but also an adjunct mechanism of its progression. The deepening knowledge of the above chain of pathogenetic events involving endothelial cells, namely increased permeability-stiffening of the matrix-endothelial dysfunction-microvascular rarefaction-tissue fibrosis, may provide a roadmap for therapeutic interventions deemed to curtail and reverse fibrosis.
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Affiliation(s)
- Michael S Goligorsky
- Department of Medicine, New York Medical College, Touro University, Valhalla, New York, United States
- Department of Pharmacology, New York Medical College, Touro University, Valhalla, New York, United States
- Department of Physiology, New York Medical College, Touro University, Valhalla, New York, United States
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Gandolfi S, Pileyre B, Drouot L, Dubus I, Auquit-Auckbur I, Martinet J. Stromal vascular fraction in the treatment of myositis. Cell Death Discov 2023; 9:346. [PMID: 37726262 PMCID: PMC10509179 DOI: 10.1038/s41420-023-01605-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2023] [Revised: 08/01/2023] [Accepted: 08/14/2023] [Indexed: 09/21/2023] Open
Abstract
Muscle regeneration is a physiological process that converts satellite cells into mature myotubes under the influence of an inflammatory environment progressively replaced by an anti-inflammatory environment, with precise crosstalk between immune and muscular cells. If the succession of these phases is disturbed, the immune system can sometimes become auto-reactive, leading to chronic muscular inflammatory diseases, such as myositis. The triggers of these autoimmune myopathies remain mostly unknown, but the main mechanisms of pathogenesis are partially understood. They involve chronic inflammation, which could be associated with an auto-reactive immune response, and gradually with a decrease in the regenerative capacities of the muscle, leading to its degeneration, fibrosis and vascular architecture deterioration. Immunosuppressive treatments can block the first part of the process, but sometimes muscle remains weakened, or even still deteriorates, due to the exhaustion of its capacities. For patients refractory to immunosuppressive therapies, mesenchymal stem cells have shown interesting effects but their use is limited by their availability. Stromal vascular fraction, which can easily be extracted from adipose tissue, has shown good tolerance and possible therapeutic benefits in several degenerative and autoimmune diseases. However, despite the increasing use of stromal vascular fraction, the therapeutically active components within this heterogeneous cellular product are ill-defined and the mechanisms by which this therapy might be active remain insufficiently understood. We review herein the current knowledge on the mechanisms of action of stromal vascular fraction and hypothesise on how it could potentially respond to some of the unmet treatment needs of refractory myositis.
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Affiliation(s)
- S Gandolfi
- Univ Rouen Normandie, INSERM U1234, FOCIS Center of Excellence PAn'THER, F-76000, Rouen, France
- Toulouse University Hospital, Department of Plastic and Reconstructive Surgery, F-31000, Toulouse, France
| | - B Pileyre
- Univ Rouen Normandie, INSERM U1234, FOCIS Center of Excellence PAn'THER, F-76000, Rouen, France.
- Centre Henri Becquerel, Department of Pharmacy, F-76000, Rouen, France.
| | - L Drouot
- Univ Rouen Normandie, INSERM U1234, FOCIS Center of Excellence PAn'THER, F-76000, Rouen, France
| | - I Dubus
- Univ Rouen Normandie, INSERM U1234, FOCIS Center of Excellence PAn'THER, F-76000, Rouen, France
| | - I Auquit-Auckbur
- Univ Rouen Normandie, INSERM U1234, FOCIS Center of Excellence PAn'THER, CHU Rouen, Department of Plastic, Reconstructive and Hand Surgery, F-76000, Rouen, France
| | - J Martinet
- Univ Rouen Normandie, INSERM U1234, FOCIS Center of Excellence PAn'THER, CHU Rouen, Department of Immunology and Biotherapy, F-76000, Rouen, France
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7
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Pechanec MY, Beall JM, Katzman S, Maga EA, Mienaltowski MJ. Examining the Effects of In Vitro Co-Culture of Equine Adipose-Derived Mesenchymal Stem Cells With Tendon Proper and Peritenon Cells. J Equine Vet Sci 2023; 126:104262. [PMID: 36841345 DOI: 10.1016/j.jevs.2023.104262] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2022] [Revised: 01/26/2023] [Accepted: 02/20/2023] [Indexed: 02/27/2023]
Abstract
Tendinopathies remain the leading contributor to career-ending injuries in horses because of the complexity of tendon repair. As such, cell-based therapies like injections of adipose-derived mesenchymal stem cells (ADMSCs, or MSCs) into injured tendons are becoming increasingly popular though their long-term efficacy on a molecular and wholistic level remains contentious. Thus, we co-cultured equine MSCs with intrinsic (tendon proper) and extrinsic (peritenon) tendon cell populations to examine interactions between these cells. Gene expression for common tenogenic, perivascular, and differentiation markers was quantified at 48 and 120 hours. Additionally, cellular metabolism of proliferation was examined every 24 hours for peritenon and tendon proper cells co-cultured with MSCs. MSCs co-cultured with tendon proper or peritenon cells had altered expression profiles demonstrating trend toward tenogenic phenotype with the exception of decreases in type I collagen (COL1A1). Peritenon cells co-cultured with MSCs had a trending and significant decrease in biglycan (BGN) and CSPG4 at 48 hours and 120 hours but overall significant increases in lysyl oxidase (LOX), mohawk (MKX), and scleraxis (SCX) within 48 hours. Tendon proper cells co-cultured with MSCs also exhibited increases in LOX and SCX at 48 hours. Furthermore, cell proliferation improved overall for tendon proper cells co-cultured with MSCs. The co-culture study results suggest that adipose-derived MSCs contribute beneficially to tenogenic stimulation of peritenon or tendon proper cells.
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Affiliation(s)
- Monica Y Pechanec
- Department of Animal Science, University of California Davis, Davis, CA
| | - Jessica M Beall
- Department of Animal Science, University of California Davis, Davis, CA
| | - Scott Katzman
- School of Veterinary Medicine, University of California Davis, Davis, CA
| | - Elizabeth A Maga
- Department of Animal Science, University of California Davis, Davis, CA
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Liu YX, Sun JM, Ho CK, Gao Y, Wen DS, Liu YD, Huang L, Zhang YF. Advancements in adipose-derived stem cell therapy for skin fibrosis. World J Stem Cells 2023; 15:342-353. [PMID: 37342214 PMCID: PMC10277960 DOI: 10.4252/wjsc.v15.i5.342] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2022] [Revised: 03/30/2023] [Accepted: 04/13/2023] [Indexed: 05/26/2023] Open
Abstract
Pathological scarring and scleroderma, which are the most common conditions of skin fibrosis, pathologically manifest as fibroblast proliferation and extracellular matrix (ECM) hyperplasia. Fibroblast proliferation and ECM hyperplasia lead to fibrotic tissue remodeling, causing an exaggerated and prolonged wound-healing response. The pathogenesis of these diseases has not been fully clarified and is unfortunately accompanied by exceptionally high medical needs and poor treatment effects. Currently, a promising and relatively low-cost treatment has emerged-adipose-derived stem cell (ASC) therapy as a branch of stem cell therapy, including ASCs and their derivatives-purified ASC, stromal vascular fraction, ASC-conditioned medium, ASC exosomes, etc., which are rich in sources and easy to obtain. ASCs have been widely used in therapeutic settings for patients, primarily for the defection of soft tissues, such as breast enhancement and facial contouring. In the field of skin regeneration, ASC therapy has become a hot research topic because it is beneficial for reversing skin fibrosis. The ability of ASCs to control profibrotic factors as well as anti-inflammatory and immunomodulatory actions will be discussed in this review, as well as their new applications in the treatment of skin fibrosis. Although the long-term effect of ASC therapy is still unclear, ASCs have emerged as one of the most promising systemic antifibrotic therapies under development.
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Affiliation(s)
- Yu-Xin Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Jia-Ming Sun
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Chia-Kang Ho
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Ya Gao
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Dong-Sheng Wen
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Yang-Dan Liu
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Lu Huang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
| | - Yi-Fan Zhang
- Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University, Shanghai 200011, China
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Helissey C, Cavallero S, Guitard N, Théry H, Chargari C, François S. Revolutionizing Radiotoxicity Management with Mesenchymal Stem Cells and Their Derivatives: A Focus on Radiation-Induced Cystitis. Int J Mol Sci 2023; 24:ijms24109068. [PMID: 37240415 DOI: 10.3390/ijms24109068] [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: 04/16/2023] [Revised: 05/02/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Although radiation therapy plays a crucial role in cancer treatment, and techniques have improved continuously, irradiation induces side effects in healthy tissue. Radiation cystitis is a potential complication following the therapeutic irradiation of pelvic cancers and negatively impacts patients' quality of life (QoL). To date, no effective treatment is available, and this toxicity remains a therapeutic challenge. In recent times, stem cell-based therapy, particularly the use of mesenchymal stem cells (MSC), has gained attention in tissue repair and regeneration due to their easy accessibility and their ability to differentiate into several tissue types, modulate the immune system and secrete substances that help nearby cells grow and heal. In this review, we will summarize the pathophysiological mechanisms of radiation-induced injury to normal tissues, including radiation cystitis (RC). We will then discuss the therapeutic potential and limitations of MSCs and their derivatives, including packaged conditioned media and extracellular vesicles, in the management of radiotoxicity and RC.
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Affiliation(s)
- Carole Helissey
- Clinical Unit Research, HIA Bégin, 69 Avenu de Paris, 94160 Saint-Mandé, France
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Sophie Cavallero
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Nathalie Guitard
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Hélène Théry
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
| | - Cyrus Chargari
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
- Department of Radiation Oncology, Pitié Salpêtrière University Hospital, 47-83 Bd de l'Hôpital, 75013 Paris, France
| | - Sabine François
- Department of Radiation Biological Effects, French Armed Forces Biomedical Research Institute, Place Général Valérie André, 91220 Brétigny-sur-Orge, France
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Molecular Mechanisms Responsible for Mesenchymal Stem Cell-Based Modulation of Obstructive Sleep Apnea. Int J Mol Sci 2023; 24:ijms24043708. [PMID: 36835120 PMCID: PMC9958695 DOI: 10.3390/ijms24043708] [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: 12/04/2022] [Revised: 01/20/2023] [Accepted: 01/26/2023] [Indexed: 02/16/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are adult stem cells that reside in almost all postnatal tissues where, due to the potent regenerative, pro-angiogenic and immunomodulatory properties, regulate tissue homeostasis. Obstructive sleep apnea (OSA) induces oxidative stress, inflammation and ischemia which recruit MSCs from their niches in inflamed and injured tissues. Through the activity of MSC-sourced anti-inflammatory and pro-angiogenic factors, MSCs reduce hypoxia, suppress inflammation, prevent fibrosis and enhance regeneration of damaged cells in OSA-injured tissues. The results obtained in large number of animal studies demonstrated therapeutic efficacy of MSCs in the attenuation of OSA-induced tissue injury and inflammation. Herewith, in this review article, we emphasized molecular mechanisms which are involved in MSC-based neo-vascularization and immunoregulation and we summarized current knowledge about MSC-dependent modulation of OSA-related pathologies.
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Meng Z, Yang T, Liu D. Type-2 epithelial-mesenchymal transition in oral mucosal nonneoplastic diseases. Front Immunol 2022; 13:1020768. [PMID: 36389753 PMCID: PMC9659919 DOI: 10.3389/fimmu.2022.1020768] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2022] [Accepted: 10/13/2022] [Indexed: 12/04/2022] Open
Abstract
The oral mucosa is a membranous structure comprising epithelial and connective tissue that covers the oral cavity. The oral mucosa is the first immune barrier to protect the body against pathogens for systemic protection. It is frequently exposed to mechanical abrasion, chemical erosion, and pathogenic invasion, resulting in oral mucosal lesions, particularly inflammatory diseases. Epithelial-mesenchymal transition (EMT) is a crucial biological process in the pathogenesis of oral mucosal disorders, which are classified into three types (types 1, 2, and 3) based on their physiological consequences. Among these, type-2 EMT is crucial in wound repair, organ fibrosis, and tissue regeneration. It causes infectious and dis-infectious immunological diseases, such as oral lichen planus (OLP), oral leukoplakia, oral submucosal fibrosis, and other precancerous lesions. However, the mechanism and cognition between type-2 EMT and oral mucosal inflammatory disorders remain unknown. This review first provides a comprehensive evaluation of type-2 EMT in chronically inflammatory oral mucosal disorders. The aim is to lay a foundation for future research and suggest potential treatments.
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Affiliation(s)
- Zhaosong Meng
- Department of Oral and Maxillofacial Surgery, Tianjin Medical University Stomatology Hospital, Tianjin, Tianjin, China
| | - Tianle Yang
- School of Stomatology, Tianjin Medical University, Tianjin, China
| | - Dayong Liu
- Department of Endodontics & Laboratory for Dental Stem Cells and Endocrine Immunology, Tianjin Medical University School of Stomatology, Tianjin, China
- *Correspondence: Dayong Liu,
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12
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Wang EY, Zhao Y, Okhovatian S, Smith JB, Radisic M. Intersection of stem cell biology and engineering towards next generation in vitro models of human fibrosis. Front Bioeng Biotechnol 2022; 10:1005051. [PMID: 36338120 PMCID: PMC9630603 DOI: 10.3389/fbioe.2022.1005051] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2022] [Accepted: 09/26/2022] [Indexed: 08/31/2023] Open
Abstract
Human fibrotic diseases constitute a major health problem worldwide. Fibrosis involves significant etiological heterogeneity and encompasses a wide spectrum of diseases affecting various organs. To date, many fibrosis targeted therapeutic agents failed due to inadequate efficacy and poor prognosis. In order to dissect disease mechanisms and develop therapeutic solutions for fibrosis patients, in vitro disease models have gone a long way in terms of platform development. The introduction of engineered organ-on-a-chip platforms has brought a revolutionary dimension to the current fibrosis studies and discovery of anti-fibrotic therapeutics. Advances in human induced pluripotent stem cells and tissue engineering technologies are enabling significant progress in this field. Some of the most recent breakthroughs and emerging challenges are discussed, with an emphasis on engineering strategies for platform design, development, and application of machine learning on these models for anti-fibrotic drug discovery. In this review, we discuss engineered designs to model fibrosis and how biosensor and machine learning technologies combine to facilitate mechanistic studies of fibrosis and pre-clinical drug testing.
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Affiliation(s)
- Erika Yan Wang
- David H. Koch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, MA, United States
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
| | - Yimu Zhao
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Sargol Okhovatian
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
| | - Jacob B. Smith
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
| | - Milica Radisic
- Institute of Biomedical Engineering, University of Toronto, Toronto, ON, Canada
- Toronto General Hospital Research Institute, University Health Network, Toronto, ON, Canada
- Department of Chemical Engineering and Applied Chemistry, University of Toronto, Toronto, ON, Canada
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13
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Ultrasound Imaging of the Superficial Fascia in the Upper Limb: Arm and Forearm. Diagnostics (Basel) 2022; 12:diagnostics12081884. [PMID: 36010234 PMCID: PMC9406830 DOI: 10.3390/diagnostics12081884] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/26/2022] [Accepted: 07/31/2022] [Indexed: 12/29/2022] Open
Abstract
The superficial fascia has received much attention in recent years due to its important role of compartmentalizing the subcutaneous tissue. Ultrasound (US) imaging, owing to its high definition, provides the possibility of better visualizing and measuring its thickness. The aim of this study was to measure and compare, with US imaging, the thickness of superficial fascia in the arm and forearm in different regions/levels. An observational study has been performed using US imaging to measure superficial fascia thickness in the anterior and posterior regions at different levels in a sample of 30 healthy volunteers. The results for superficial fascia thickness revealed statistically significant differences (p < 0.0001) in the arm between the anterior and posterior regions; in terms of forearm, some statistically significant differences were found between regions/levels. However, in the posterior region/levels of the arm, the superficial fascia was thicker (0.53 ± 0.10 mm) than in the forearm (0.41 ± 0.10 mm); regarding the anterior regions/levels, the superficial fascia of the arm (0.40 ± 0.10 mm) was not statistically different than the forearm (0.40 ± 0.12 mm). In addition, the intra-rater reliability was good (ICC2,k: 0.88). US helps to visualize and assess the superficial fascia inside the subcutaneous tissue, improving the diagnosis of fascial dysfunction, and one of the Us parameters to reliably assess is the thickness in different regions and levels.
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14
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Qu W, Wang Z, Engelberg-Cook E, Yan D, Siddik AB, Bu G, Allickson JG, Kubrova E, Caplan AI, Hare JM, Ricordi C, Pepine CJ, Kurtzberg J, Pascual JM, Mallea JM, Rodriguez RL, Nayfeh T, Saadi S, Durvasula RV, Richards EM, March K, Sanfilippo FP. Efficacy and Safety of MSC Cell Therapies for Hospitalized Patients with COVID-19: A Systematic Review and Meta-Analysis. Stem Cells Transl Med 2022; 11:688-703. [PMID: 35640138 PMCID: PMC9299515 DOI: 10.1093/stcltm/szac032] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 03/09/2022] [Indexed: 08/10/2023] Open
Abstract
MSC (a.k.a. mesenchymal stem cell or medicinal signaling cell) cell therapies show promise in decreasing mortality in acute respiratory distress syndrome (ARDS) and suggest benefits in treatment of COVID-19-related ARDS. We performed a meta-analysis of published trials assessing the efficacy and adverse events (AE) rates of MSC cell therapy in individuals hospitalized for COVID-19. Systematic searches were performed in multiple databases through November 3, 2021. Reports in all languages, including randomized clinical trials (RCTs), non-randomized interventional trials, and uncontrolled trials, were included. Random effects model was used to pool outcomes from RCTs and non-randomized interventional trials. Outcome measures included all-cause mortality, serious adverse events (SAEs), AEs, pulmonary function, laboratory, and imaging findings. A total of 736 patients were identified from 34 studies, which included 5 RCTs (n = 235), 7 non-randomized interventional trials (n = 370), and 22 uncontrolled comparative trials (n = 131). Patients aged on average 59.4 years and 32.2% were women. When compared with the control group, MSC cell therapy was associated with a reduction in all-cause mortality (RR = 0.54, 95% CI: 0.35-0.85, I 2 = 0.0%), reduction in SAEs (IRR = 0.36, 95% CI: 0.14-0.90, I 2 = 0.0%) and no significant difference in AE rate. A sub-group with pulmonary function studies suggested improvement in patients receiving MSC. These findings support the potential for MSC cell therapy to decrease all-cause mortality, reduce SAEs, and improve pulmonary function compared with conventional care. Large-scale double-blinded, well-powered RCTs should be conducted to further explore these results.
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Affiliation(s)
- Wenchun Qu
- Corresponding co-authors: Wenchun Qu, MD, PhD, Department of Pain Medicine, Mayo Clinic Florida, 4500 San Pablo Road, Jacksonville, FL 32224.
| | - Zhen Wang
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | | | - Dan Yan
- Department of Pain Medicine, Mayo Clinic, Jacksonville, FL, USA
| | | | - Guojun Bu
- Center for Regenerative Medicine, Mayo Clinic, Jacksonville, FL, USA
- Department of Neuroscience, Mayo Clinic, Jacksonville, FL, USA
| | | | - Eva Kubrova
- Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN, USA
| | - Arnold I Caplan
- Skeletal Research Center, Biology Department, Case Western Reserve University, Cleveland, OH, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute and Cardiology Division, Department of Medicine, University of Miami, Miller School of Medicine, Miami, FL, USA
| | - Camillo Ricordi
- Department of Surgery, Diabetes Research Institute and Cell Transplant Center, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Carl J Pepine
- Division of Cardiovascular Medicine, and Center for Regenerative Medicine, University of Florida, Gainesville, FL, USA
| | - Joanne Kurtzberg
- Marcus Center for Cellular Cures, Duke University School of Medicine, Durham, NC, USA
| | - Jorge M Pascual
- Division of Pulmonary, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | - Jorge M Mallea
- Division of Pulmonary, Allergy and Sleep Medicine, Department of Medicine, Mayo Clinic, Jacksonville, FL, USA
| | | | - Tarek Nayfeh
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | - Samer Saadi
- Evidence-Based Practice Center, Mayo Clinic, Rochester, MN, USA
- Robert D. and Patricia E. Kern Center for the Science of Health Care Delivery, Mayo Clinic, Rochester, MN, USA
| | | | - Elaine M Richards
- Department of Physiology and Functional Genomics, Center of Regenerative Medicine, University of Florida, Gainesville, FL, USA
| | - Keith March
- Division of Cardiovascular Medicine, and Center for Regenerative Medicine, University of Florida, Gainesville, FL, USA
| | - Fred P Sanfilippo
- Fred P. Sanfilippo, MD, PhD, Pathology and Laboratory Medicine, School of Medicine, Emory University, 1518 Clifton Road, 730GCR, Atlanta, GA 30322, USA.
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15
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Clinical Application of Induced Hepatocyte-like Cells Produced from Mesenchymal Stromal Cells: A Literature Review. Cells 2022; 11:cells11131998. [PMID: 35805080 PMCID: PMC9265349 DOI: 10.3390/cells11131998] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Revised: 06/15/2022] [Accepted: 06/16/2022] [Indexed: 11/17/2022] Open
Abstract
Liver disease is a leading cause of mortality worldwide, resulting in 1.3 million deaths annually. The vast majority of liver disease is caused by metabolic disease (i.e., NASH) and alcohol-induced hepatitis, and to a lesser extent by acute and chronic viral infection. Furthermore, multiple insults to the liver is becoming common due to the prevalence of metabolic and alcohol-related liver diseases. Despite this rising prevalence of liver disease, there are few treatment options: there are treatments for viral hepatitis C and there is vaccination for hepatitis B. Aside from the management of metabolic syndrome, no direct liver therapy has shown clinical efficacy for metabolic liver disease, there is very little for acute alcohol-induced liver disease, and liver transplantation remains the only effective treatment for late-stage liver disease. Traditional pharmacologic interventions have failed to appreciably impact the pathophysiology of alcohol-related liver disease or end-stage liver disease. The difficulties associated with developing liver-specific therapies result from three factors that are common to late-stage liver disease arising from any cause: hepatocyte injury, inflammation, and aberrant tissue healing. Hepatocyte injury results in tissue damage with inflammation, which sensitizes the liver to additional hepatocyte injury and stimulates hepatic stellate cells and aberrant tissue healing responses. In the setting of chronic liver insults, there is progressive scarring, the loss of hepatocyte function, and hemodynamic dysregulation. Regenerative strategies using hepatocyte-like cells that are manufactured from mesenchymal stromal cells may be able to correct this pathophysiology through multiple mechanisms of action. Preclinical studies support their effectiveness and recent clinical studies suggest that cell replacement therapy can be safe and effective in patients with liver disease for whom there is no other option.
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16
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Role and Function of Mesenchymal Stem Cells on Fibroblast in Cutaneous Wound Healing. Biomedicines 2022; 10:biomedicines10061391. [PMID: 35740413 PMCID: PMC9219688 DOI: 10.3390/biomedicines10061391] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2022] [Revised: 06/06/2022] [Accepted: 06/10/2022] [Indexed: 11/24/2022] Open
Abstract
Skin wounds often repair themselves completely over time; however, this is true only for healthy individuals. Although various studies are being conducted to improve wound-healing therapy outcomes, the mechanisms of wound healing and regeneration are not completely understood yet. In recent years, mesenchymal stem cells (MSCs) have been reported to contribute significantly to wound healing and regeneration. Understanding the function of MSCs will help to elucidate the fundamentals of wound healing. MSCs are multipotent stem cells that are used in regenerative medicine for their ability to self-renew and differentiate into bone, fat, and cartilage, with few ethical problems associated with cell harvesting. Additionally, they have anti-inflammatory and immunomodulatory properties and antifibrotic effects via paracrine signaling, and many studies have been conducted to use them to treat graft-versus-host disease, inflammatory bowel disease, and intractable cutaneous wounds. Many substances derived from MSCs are involved in the wound-healing process, and specific cascades and pathways have been elucidated. This review aims to explain the fundamental role of MSCs in wound healing and the effects of MSCs on fibroblasts.
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17
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Li C, Wang B. Mesenchymal Stem/Stromal Cells in Progressive Fibrogenic Involvement and Anti-Fibrosis Therapeutic Properties. Front Cell Dev Biol 2022; 10:902677. [PMID: 35721482 PMCID: PMC9198494 DOI: 10.3389/fcell.2022.902677] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Accepted: 05/13/2022] [Indexed: 11/22/2022] Open
Abstract
Fibrosis refers to the connective tissue deposition and stiffness usually as a result of injury. Fibrosis tissue-resident mesenchymal cells, including fibroblasts, myofibroblast, smooth muscle cells, and mesenchymal stem/stromal cells (MSCs), are major players in fibrogenic processes under certain contexts. Acknowledging differentiation potential of MSCs to the aforementioned other types of mesenchymal cell lineages is essential for better understanding of MSCs’ substantial contributions to progressive fibrogenesis. MSCs may represent a potential therapeutic option for fibrosis resolution owing to their unique pleiotropic functions and therapeutic properties. Currently, clinical trial efforts using MSCs and MSC-based products are underway but clinical data collected by the early phase trials are insufficient to offer better support for the MSC-based anti-fibrotic therapies. Given that MSCs are involved in the coagulation through releasing tissue factor, MSCs can retain procoagulant activity to be associated with fibrogenic disease development. Therefore, MSCs’ functional benefits in translational applications need to be carefully balanced with their potential risks.
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Affiliation(s)
- Chenghai Li
- Stem Cell Program of Clinical Research Center, People’s Hospital of Zhengzhou University and Henan Provincial People’s Hospital, Zhengzhou, China
- Henan Key Laboratory of Stem Cell Differentiation and Modification, Henan University, Zhengzhou, China
- *Correspondence: Chenghai Li, ; Bin Wang,
| | - Bin Wang
- Department of Neurosurgery, People’s Hospital of Zhengzhou University and Henan Provincial People’s Hospital, Zhengzhou, China
- *Correspondence: Chenghai Li, ; Bin Wang,
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18
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Yang YP, Lai WY, Lin TW, Lin YY, Chien Y, Tsai YC, Tai HY, Wang CL, Liu YY, Huang PI, Chen YW, Lo WL, Wang CY. Autophagy reprogramming stem cell pluripotency and multiple-lineage differentiation. J Chin Med Assoc 2022; 85:667-671. [PMID: 35385421 DOI: 10.1097/jcma.0000000000000728] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The cellular process responsible for the degradation of cytosolic proteins and subcellular organelles in lysosomes was termed "autophagy." This process occurs at a basal level in most tissues as part of tissue homeostasis that redounds to the regular turnover of components inside cytoplasm. The breakthrough in the autophagy field is the identification of key players in the autophagy pathway, compounded under the name "autophagy-related genes" (ATG) encoding for autophagy effector proteins. Generally, the function of autophagy can be classified into two divisions: intracellular clearance of defective macromolecules and organelles and generation of degradation products. Therapeutic strategies using stem cell-based approach come as a promising therapy and develop rapidly recently as stem cells have high self-renewability and differentiation capability as known as mesenchymal stem cells (MSCs). They are defined as adherent fibroblast-like population with the abilities to self-renew and multi-lineage differentiate into osteogenic, adipogenic, and chondrogenic lineage cells. To date, they are the most extensively applied adult stem cells in clinical trials. The properties of MSCs, such as immunomodulation, neuroprotection, and tissue repair pertaining to cell differentiation, processes to replace lost, or damaged cells, for aiding cell repair and revival. Autophagy has been viewed as a remarkable mechanism for maintaining homeostasis, ensuring the adequate function and survival of long-lived stem cells. In addition, authophagy also plays a remarkable role in protecting stem cells against cellular stress when the stem cell regenerative capacity is harmed in aging and cellular degeneration. Understanding the under-explored mechanisms of MSC actions and expanding the spectrum of their clinical applications may improve the utility of the MSC-based therapeutic approach in the future.
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Affiliation(s)
- Yi-Ping Yang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Wei-Yi Lai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Tzu-Wei Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Ying Lin
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yueh Chien
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Institute of Pharmacology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Yi-Ching Tsai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Hsiao-Yun Tai
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Chia-Lin Wang
- Department of Medical Research, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yung-Yang Liu
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Chest Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Pin-I Huang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Yi-Wei Chen
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Cancer Center, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
| | - Wen-Liang Lo
- Institute of Oral Biology, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Division of Oral and Maxillofacial Surgery, Department of Stomatology, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Dentistry, School of Dentistry, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
| | - Chien-Ying Wang
- School of Medicine, National Yang Ming Chiao Tung University, Taipei, Taiwan, ROC
- Department of Critical Care Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Division of Trauma, Department of Emergency Medicine, Taipei Veterans General Hospital, Taipei, Taiwan, ROC
- Department of Physical Education and Health, University of Taipei, Taipei, Taiwan, ROC
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19
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Lee B, Dane B, Katz S. Current and Emerging Approaches to the Diagnosis and Treatment of Crohn's Disease Strictures. Gastroenterol Hepatol (N Y) 2022; 18:186-195. [PMID: 35505943 PMCID: PMC9053491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
The management and understanding of Crohn's disease (CD) continues to evolve quickly. Intestinal strictures were previously thought to be an inevitable result of irreversible fibrosis caused by chronic inflammation. However, increased understanding of the dynamic nature of strictures and of the pathophysiology of this condition has highlighted emerging targets for potential treatment. In the diagnosis of strictures, a distinction must be made between inflammatory and fibrotic types, as the former may respond to medical therapy. Emerging technologies, such as dual-energy computed tomography enterography and iodine density, have allowed more accurate characterization of strictures. Surgical and endoscopic treatment remains the mainstay for fibrotic strictures, but developments in systemic and intralesional biologic therapy have shown efficacy. This article reviews the pathophysiology of this debilitating complication of CD as well as current and emerging diagnostics and treatments.
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Affiliation(s)
- Briton Lee
- Department of Medicine, NYU Langone Medical Center, New York, New York
| | - Bari Dane
- Department of Radiology, NYU Langone Medical Center, New York, New York
| | - Seymour Katz
- Department of Gastroenterology, NYU Langone Medical Center, New York, New York
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20
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Vieujean S, Loly JP, Boutaffala L, Meunier P, Reenaers C, Briquet A, Lechanteur C, Baudoux E, Beguin Y, Louis E. Mesenchymal Stem Cell Injection in Crohn's Disease Strictures: A Phase I-II Clinical Study. J Crohns Colitis 2022; 16:506-510. [PMID: 34473270 DOI: 10.1093/ecco-jcc/jjab154] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND AND AIM Mesenchymal stem cells [MSCs] have anti-inflammatory and anti-fibrotic properties and could be a potential therapy for Crohn's disease [CD] strictures. In this phase I-II pilot trial, we assessed safety and efficacy of local MSC injection to treat CD strictures. METHODS CD patients with a short [less than 5 cm in length] non-passable stricture accessible by ileocolonoscopy were included. Allogenic bone-marrow derived MSCs were injected in the four quadrants of the stricture. Adverse events and clinical scores were evaluated at each follow-up visit and endoscopy and magnetic resonance enterography were performed at baseline, Week [W]12 and W48. The main judgement criterion for efficacy was the complete [defined by the ability to pass the ileocolonoscope] or partial [defined by a diameter increase] resolution of the stricture at W12. Second efficacy criteria included assessment of the stricture at W48 and evolution of clinical scores at W12 and W48. RESULTS We performed 11 MSC injections in 10 CD patients [three primary and seven anastomotic strictures; one stricture injected twice]. MSC injections were well tolerated but four hospitalisations for occlusion were reported. At W12, five patients presented a complete or partial resolution of the stricture [two complete and three partial]. Seven patients were re-evaluated at W48 [one dilated, one operated, and one lost to follow-up] and four patients had a complete resolution. The evolution of clinical scores between W0, W12, and W48 was not statistically significant. CONCLUSIONS MSCs injection in CD stricture was well tolerated and may offer a benefit.
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Affiliation(s)
- Sophie Vieujean
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Jean-Philippe Loly
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Layla Boutaffala
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Paul Meunier
- Department of Radiology, University Hospital CHU of Liège, Liège, Belgium
| | - Catherine Reenaers
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
| | - Alexandra Briquet
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium
| | - Chantal Lechanteur
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium
| | - Etienne Baudoux
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium
| | - Yves Beguin
- Laboratory of Cell and Gene Therapy [LTCG], University Hospital CHU of Liège, Liège, Belgium.,Department of Hematology, University Hospital CHU of Liège and University of Liège, Liège, Belgium
| | - Edouard Louis
- Hepato-Gastroenterology and Digestive Oncology, University Hospital CHU of Liège, Liège, Belgium
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21
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Burk J, Sassmann A, Kasper C, Nimptsch A, Schubert S. Extracellular Matrix Synthesis and Remodeling by Mesenchymal Stromal Cells Is Context-Sensitive. Int J Mol Sci 2022; 23:ijms23031758. [PMID: 35163683 PMCID: PMC8836208 DOI: 10.3390/ijms23031758] [Citation(s) in RCA: 15] [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: 11/30/2021] [Revised: 01/25/2022] [Accepted: 01/29/2022] [Indexed: 12/17/2022] Open
Abstract
Matrix remodeling could be an important mode of action of multipotent mesenchymal stromal cells (MSC) in extracellular matrix (ECM) disease, but knowledge is limited in this respect. As MSC are well-known to adapt their behavior to their environment, we aimed to investigate if their mode of action would change in response to healthy versus pathologically altered ECM. Human MSC-derived ECM was produced under different culture conditions, including standard culture, culture on Matrigel-coated dishes, and stimulation with the pro-fibrotic transforming growth factor-β1 (TGFβ1). The MSC-ECM was decellularized, characterized by histochemistry, and used as MSC culture substrate reflecting different ECM conditions. MSC were cultured on the different ECM substrates or in control conditions for 2 days. Culture on ECM increased the presence of surface molecules with ECM receptor function in the MSC, demonstrating an interaction between MSC and ECM. In MSC cultured on Matrigel-ECM and TGFβ1-ECM, which displayed a fibrosis-like morphology, gene expression of collagens and decorin, as well as total matrix metalloproteinase (MMP) activity in the supernatant were decreased as compared with control conditions. These results demonstrated that MSC adapt to their ECM environment, which may include pathological adaptations that could compromise therapeutic efficacy.
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Affiliation(s)
- Janina Burk
- Equine Clinic (Surgery, Orthopedics), Justus-Liebig-University Giessen, 35392 Giessen, Germany
- Institute for Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), 1190 Vienna, Austria; (A.S.); (C.K.)
- Correspondence:
| | - Anna Sassmann
- Institute for Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), 1190 Vienna, Austria; (A.S.); (C.K.)
| | - Cornelia Kasper
- Institute for Cell and Tissue Culture Technologies, Department of Biotechnology, University of Natural Resources and Life Sciences (BOKU), 1190 Vienna, Austria; (A.S.); (C.K.)
| | - Ariane Nimptsch
- Institute for Medical Physics and Biophysics, University of Leipzig, 04107 Leipzig, Germany;
| | - Susanna Schubert
- Institute of Human Genetics, University of Leipzig, 04103 Leipzig, Germany;
- Saxon Incubator for Clinical Translation, University of Leipzig, 04103 Leipzig, Germany
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22
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Elliot SJ, Catanuto P, Pereira-Simon S, Xia X, Pastar I, Thaller S, Head CR, Stojadinovic O, Tomic-Canic M, Glassberg MK. Catalase, a therapeutic target in the reversal of estrogen-mediated aging. Mol Ther 2022; 30:947-962. [PMID: 34174444 PMCID: PMC8821897 DOI: 10.1016/j.ymthe.2021.06.020] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 01/30/2021] [Accepted: 06/09/2021] [Indexed: 02/04/2023] Open
Abstract
Despite increasing interest in the reversal of age-related processes, there is a paucity of data regarding the effects of post-menopausal-associated estrogen loss on cellular function. We studied human adipose-derived mesenchymal stem cells (hASCs) isolated from women younger than 45 years old (pre-menopause, pre-hASC) or older than 55 years old (post-menopause, post-hASC). In this study, we provide proof of concept that the age-related ineffective functionality of ASCs can be reversed to improve their ability in promoting tissue repair. We found reduced estrogen receptor expression, decreased estrogen receptor activation, and reduced sensitivity to 17β-estradiol in post-hASCs. This correlated with decreased antioxidants (catalase and superoxide dismutase [SOD] expression) and increased oxidative stress compared with pre-hASCs. Increasing catalase expression in post-hASCs restored estrogen receptor (ER) expression and their functional capacity to promote tissue repair as shown in human skin ex vivo wound healing and in vivo mouse model of lung injury. Our results suggest that the consequences of 17β-estradiol decline on the function of hASCs may be reversible by changing the oxidative stress/antioxidant composition.
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Affiliation(s)
- Sharon J. Elliot
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Corresponding author: Sharon J. Elliot, DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA.
| | - Paola Catanuto
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Simone Pereira-Simon
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Xiaomei Xia
- Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA
| | - Irena Pastar
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Seth Thaller
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Cheyanne R. Head
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Olivera Stojadinovic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marjana Tomic-Canic
- Wound Healing and Regenerative Medicine Research Program, Department of Dermatology and Cutaneous Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA
| | - Marilyn K. Glassberg
- DeWitt Daughtry Family Department of Surgery, University of Miami Leonard M. Miller School of Medicine, Miami, FL 33136, USA,Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA,Corresponding author: Marilyn K. Glassberg, Department of Medicine, Division of Pulmonary, Critical Care, and Sleep, University of Arizona College of Medicine, Phoenix, AZ 85004, USA.
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23
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Swarup A, Ta CN, Wu AY. Molecular mechanisms and treatments for ocular symblephara. Surv Ophthalmol 2022; 67:19-30. [PMID: 33932469 PMCID: PMC8553799 DOI: 10.1016/j.survophthal.2021.04.008] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2020] [Revised: 04/16/2021] [Accepted: 04/19/2021] [Indexed: 01/03/2023]
Abstract
There are currently no effective methods to prevent or durably treat ocular symblephara, the adhesions between the palpebral and bulbar conjunctiva. How symblephara form at the molecular level is largely unknown. We present here an overview of current clinical symblephara treatments and describe potential molecular mechanisms behind conjunctival adhesion formation that may inform future symblephara treatment and prevention options. Understanding how symblephara form at the molecular level will facilitate treatment development. Preventative therapies may be possible by targeting symblephara progenitor cells immediately after injuries, while novel therapeutics should be aimed at modulating TGF-β pathways and effector cells in conjunctival scarring to treat symblephara formation more effectively.
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Affiliation(s)
- Aditi Swarup
- Department of Ophthalmology, Stanford University School of Medicine
| | - Christopher N Ta
- Department of Ophthalmology, Stanford University School of Medicine
| | - Albert Y Wu
- Department of Ophthalmology, Stanford University School of Medicine.
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24
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Khan K, Makhoul G, Yu B, Jalani G, Derish I, Rutman AK, Cerruti M, Schwertani A, Cecere R. Amniotic stromal stem cell-loaded hydrogel repairs cardiac tissue in infarcted rat hearts via paracrine mediators. J Tissue Eng Regen Med 2021; 16:110-127. [PMID: 34726328 DOI: 10.1002/term.3262] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 09/18/2021] [Accepted: 10/19/2021] [Indexed: 11/07/2022]
Abstract
The use of stem cells to repair the heart after a myocardial infarction (MI) remains promising, yet clinical trials over the past 20 years suggest that cells fail to integrate into the native tissue, resulting in limited improvements in cardiac function. Here, we demonstrate the cardioprotective potential of a composite inserting human amniotic stromal mesenchymal stem cells (ASMCs) in a chitosan and hyaluronic acid (C/HA) based hydrogel in a rat MI model. Mechanical characterization of the C/HA platform indicated a swift elastic conversion at 40°C and a rapid sol-gel transition time at 37°C. Cell viability assay presented active and proliferating AMSCs in the C/HA. The ASMCs + C/HA injected composite significantly increased left ventricular ejection fraction, fractional shortening, and neovessel formation. The encapsulated AMSCs were abundantly detected in the infarcted myocardium 6 weeks post-administration and co-expressed cardiac proteins and notably proliferative markers. Proteomic profiling revealed that extracellular vesicles released from hypoxia preconditioned ASMCs contained proteins involved in cytoprotection, angiogenesis, cardiac differentiation and non-canonical Wnt-signaling. Independent activation of non-canonical Wnt-signaling pathways in ASMCs induced cardiogenesis. Despite a low injected cellular density at baseline, the encapsulated AMSCs were abundantly retained and increased cardiac function. Furthermore, the C/HA hydrogel provided an active milieu for the AMSCs to proliferate, co-express cardiac proteins, and induce new vessel formation. Hence, this novel composite of AMSCs + C/HA scaffold is a conceivable candidate that could restore cardiac function and reduce remodeling.
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Affiliation(s)
- Kashif Khan
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Georges Makhoul
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Bin Yu
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Ghulam Jalani
- Department of Mining and Materials Engineering, McGill University, Montreal, Quebec, Canada
| | - Ida Derish
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Alissa K Rutman
- Human Islet Transplant Laboratory, Department of Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Marta Cerruti
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Adel Schwertani
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada
| | - Renzo Cecere
- Divisions of Cardiology and Cardiac Surgery, McGill University Health Centre, Montreal, Quebec, Canada.,The Royal Victoria Hospital Montreal, Montreal, Quebec, Canada
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25
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Hezam K, Mo R, Wang C, Liu Y, Li Z. Anti-inflammatory Effects of Mesenchymal Stem Cells and Their Secretomes in Pneumonia. Curr Pharm Biotechnol 2021; 23:1153-1167. [PMID: 34493193 DOI: 10.2174/1389201022666210907115126] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2021] [Revised: 07/23/2021] [Accepted: 07/26/2021] [Indexed: 11/22/2022]
Abstract
Mesenchymal stem cells (MSCs) are multipotent progenitor cells that play crucial roles in the microenvironment of injured tissues. The potential therapeutics of MSCs have attracted extensive attention for several diseases such as acute respiratory distress syndrome (ARDS) and novel coronavirus disease 2019 (COVID-19) pneumonia. MSC-extracellular vesicles have been isolated from MSC-conditioned media (MSC-CM) with similar functional effects as parent MSCs. The therapeutic role of MSCs can be achieved through the balance between the inflammatory and regenerative microenvironments. Clinical settings of MSCs and their extracellular vesicles remain promising for many diseases, such as ARDS and pneumonia. However, their clinical applications remain limited due to the cost of growing and storage facilities of MSCs with a lack of standardized MSC-CM. This review highlights the proposed role of MSCs in pulmonary diseases and discusses the recent advances of MSC application for pneumonia and other lung disorders.
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Affiliation(s)
- Kamal Hezam
- Nankai University School of Medicine, Tianjin. China
| | - Rigen Mo
- Nankai University School of Medicine, Tianjin. China
| | - Chen Wang
- Nankai University School of Medicine, Tianjin. China
| | - Yue Liu
- Nankai University School of Medicine, Tianjin. China
| | - Zongjin Li
- Nankai University School of Medicine, Tianjin. China
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26
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Mostafa A, Altaib Z, Sayed W, Rashwan E, Albrakati A. Bone Marrow-derived Mesenchymal Stem Cells Reverse Hepatic Fibrosis, Improved Vascularity, and Attenuate the Apoptosis in Carbon Tetrachloride-induced Hepatic Fibrosis Experimental Rats. Open Access Maced J Med Sci 2021. [DOI: 10.3889/oamjms.2021.6590] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Background: Liver fibrosis is a sequel of different chronic inflammatory diseases. The most effective treatment for end-stage liver fibrosis is liver transplantation; but the shortage of donor organs, immunological rejection, surgical complications, and high medical costs limit the transplantation. That’s why we are in argent need to develop new strategies in treatment. Objectives: to evaluate the role of MSCs in regenerating liver cells and reverse hepatic fibrosis. Materials and Methods: 30 Animals were randomly divided into three groups (10 animals each): group 1: a negative control; group 2: induced liver fibrosis (pathological control).; group 3: induced liver fibrosis that received undifferentiated BM MSCs (3×106 cells/ml intraperitoneally/single dose); The extent of fibrosis, vascularization, and inflammation and hepatic cell apoptosis were evaluated together with assessment of liver functions. Results: The MSCs treated group showed significant improvement of liver functions, and attenuation of fibrosis histopathologicaly and down regulate the expression of TGF ß versus the induced fibrosis group. inflammatory marker(TNF,IL-6) were down regulated and vascularity was restored in MSCs treated group compared to CCL4 induced fibrosis rats. Conclusion: MSCs provide promising therapeutic agents in treatment of liver fibrosis.
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27
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Efimenko AY, Kalinina NI, Rubina KA, Semina EV, Sysoeva VY, Akopyan ZA, Tkachuk VA. Secretome of Multipotent Mesenchymal Stromal Cells as a Promising Treatment and for Rehabilitation of Patients with the Novel Coronaviral Infection. HERALD OF THE RUSSIAN ACADEMY OF SCIENCES 2021; 91:170-175. [PMID: 34131372 PMCID: PMC8192105 DOI: 10.1134/s101933162102012x] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/25/2020] [Revised: 12/28/2020] [Accepted: 01/30/2021] [Indexed: 06/12/2023]
Abstract
As a rule, coronavirus infections are mild in healthy adults and do not require special approaches to treatment. However, highly pathogenic strains, particularly the recently isolated SARS-CoV2, which causes COVID-19 infection, in about 15% of cases lead to severe complications, including acute respiratory distress syndrome, which causes high patient mortality. In addition, a common complication of COVID-19 is the development of pulmonary fibrosis. Why is the novel coronavirus so pathogenic? What new treatments can be proposed to speed up the recovery and subsequent rehabilitation of the organism? In 2020, over 34 000 scientific articles were published on the structure, distribution, pathogenesis, and possible approaches to the treatment of infection caused by the novel SARS-CoV2 coronavirus. However, there are still no definitive answers to these questions, while the number of the diseased is increasing daily. One of the comprehensive approaches to the treatment of the consequences of the infection is the use of multipotent human mesenchymal stromal cells and products of their secretion (secretome). Acting at several stages of the development of the infection, the components of the secretome can suppress the interaction of the virus with endothelial cells, regulate inflammation, and stimulate lung tissue regeneration, preventing the development of fibrosis. The results of basic and clinical research on this topic are summarized, including our own experimental data, indicating that cell therapy approaches can be successfully applied to treat patients with COVID-19.
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Affiliation(s)
- A. Yu. Efimenko
- Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Educational Center, Moscow State University, Moscow, Russia
| | | | | | - E. V. Semina
- Moscow State University, Moscow, Russia
- National Medical Research Center of Cardiology, Ministry of Health of Russia, Moscow, Russia
| | | | - Zh. A. Akopyan
- Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Educational Center, Moscow State University, Moscow, Russia
| | - V. A. Tkachuk
- Moscow State University, Moscow, Russia
- Institute for Regenerative Medicine, Medical Research and Educational Center, Moscow State University, Moscow, Russia
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28
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Coimbra-Campos LMC, Silva WN, Baltazar LM, Costa PAC, Prazeres PHDM, Picoli CC, Costa AC, Rocha BGS, Santos GSP, Oliveira FMS, Pinto MCX, Amorim JH, Azevedo VAC, Souza DG, Russo RC, Resende RR, Mintz A, Birbrair A. Circulating Nestin-GFP + Cells Participate in the Pathogenesis of Paracoccidioides brasiliensis in the Lungs. Stem Cell Rev Rep 2021; 17:1874-1888. [PMID: 34003465 DOI: 10.1007/s12015-021-10181-3] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 05/06/2021] [Indexed: 02/06/2023]
Abstract
Multiple infectious diseases lead to impaired lung function. Revealing the cellular mechanisms involved in this impairment is crucial for the understanding of how the lungs shift from a physiologic to a pathologic state in each specific condition. In this context, we explored the pathogenesis of Paracoccidioidomycosis, which affects pulmonary functioning. The presence of cells expressing Nestin-GFP has been reported in different tissues, and their roles as tissue-specific progenitors have been stablished in particular organs. Here, we explored how Nestin-GFP+ cells are affected after lung infection by Paracoccidioides brasiliensis, a model of lung granulomatous inflammation with fibrotic outcome. We used Nestin-GFP transgenic mice, parabiosis surgery, confocal microscopy and flow cytometry to investigate the participation of Nestin-GFP+ cells in Paracoccidioides brasiliensis pathogenesis. We revealed that these cells increase in the lungs post-Paracoccidioides brasiliensis infection, accumulating around granulomas. This increase was due mainly to Nestin-GPF+ cells derived from the blood circulation, not associated to blood vessels, that co-express markers suggestive of hematopoietic cells (Sca-1, CD45 and CXCR4). Therefore, our findings suggest that circulating Nestin-GFP+ cells participate in the Paracoccidioides brasiliensis pathogenesis in the lungs.
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Affiliation(s)
| | - Walison N Silva
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Ludmila M Baltazar
- Department of Microbiology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Pedro A C Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Pedro H D M Prazeres
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Caroline C Picoli
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Alinne C Costa
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Beatriz G S Rocha
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Gabryella S P Santos
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Fabrício M S Oliveira
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Mauro C X Pinto
- Laboratory of Neuropharmacology and Neurochemistry, Institute of Biological Sciences, Federal University of Goiás, Goiânia, GO, Brazil
| | - Jaime H Amorim
- Center of Biological Sciences and Health, Federal University of West Bahia, Barreiras, BA, Brazil
| | - Vasco A C Azevedo
- Cellular and Molecular Genetics Laboratory, Department of Genetics, Ecology and Evolution, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Danielle G Souza
- Department of Microbiology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Remo C Russo
- Laboratory of Pulmonary Immunology and Mechanics, Department of Physiology and Biophysics, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Rodrigo R Resende
- Department of Biochemistry and Immunology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Akiva Mintz
- Department of Radiology, Columbia University Medical Center, New York, NY, USA
| | - Alexander Birbrair
- Department of Pathology, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil.
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29
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Semenova E, Grudniak MP, Machaj EK, Bocian K, Chroscinska-Krawczyk M, Trochonowicz M, Stepaniec IM, Murzyn M, Zagorska KE, Boruczkowski D, Kolanowski TJ, Oldak T, Rozwadowska N. Mesenchymal Stromal Cells from Different Parts of Umbilical Cord: Approach to Comparison & Characteristics. Stem Cell Rev Rep 2021; 17:1780-1795. [PMID: 33860454 PMCID: PMC8553697 DOI: 10.1007/s12015-021-10157-3] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/17/2021] [Indexed: 02/06/2023]
Abstract
Mesenchymal stromal/stem cells (MSCs) are a unique population of cells that play an important role in the regeneration potential of the body. MSCs exhibit a characteristic phenotype and are capable of modulating the immune response. MSCs can be isolated from various tissues such as: bone marrow, adipose tissue, placenta, umbilical cord and others. The umbilical cord as a source of MSCs, has strong advantages, such as no-risk procedure of tissue retrieval after birth and easiness of the MSCs isolation. As the umbilical cord (UC) is a complex organ and we decided to evaluate, whether the cells derived from different regions of umbilical cord show similar or distinct properties. In this study we characterized and compared MSCs from three regions of the umbilical cord: Wharton's Jelly (WJ), the perivascular space (PRV) and the umbilical membrane (UCM). The analysis was carried out in terms of morphology, phenotype, immunomodulation potential and secretome. Based on the obtained results, we were able to conclude, that MSCs derived from distinct UC regions differ in their properties. According to our result WJ-MSCs have high and stabile proliferation potential and phenotype, when compare with other MSCs and can be treated as a preferable source of cells for medical application.
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Affiliation(s)
- Ekaterina Semenova
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Mariusz P Grudniak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Eugeniusz K Machaj
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Katarzyna Bocian
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Faculty of Biology, Department of Immunology, University of Warsaw, Warsaw, Poland
| | | | - Marzena Trochonowicz
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Igor M Stepaniec
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Magdalena Murzyn
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Karolina E Zagorska
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Dariusz Boruczkowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland
| | - Tomasz J Kolanowski
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.,Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Tomasz Oldak
- Research and Development Department, Polish Stem Cell Bank, FamiCord Group, Ul. Jana Pawla II 29, 00-867, Warsaw, Poland.
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30
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Cimini M, Kishore R. Role of Podoplanin-Positive Cells in Cardiac Fibrosis and Angiogenesis After Ischemia. Front Physiol 2021; 12:667278. [PMID: 33912076 PMCID: PMC8072458 DOI: 10.3389/fphys.2021.667278] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Accepted: 03/15/2021] [Indexed: 01/05/2023] Open
Abstract
New insights into the cellular and extra-cellular composition of scar tissue after myocardial infarction (MI) have been identified. Recently, a heterogeneous podoplanin-expressing cell population has been associated with fibrogenic and inflammatory responses and lymphatic vessel growth during scar formation. Podoplanin is a mucin-like transmembrane glycoprotein that plays an important role in heart development, cell motility, tumorigenesis, and metastasis. In the adult mouse heart, podoplanin is expressed only by cardiac lymphatic endothelial cells; after MI, it is acquired with an unexpected heterogeneity by PDGFRα-, PDGFRβ-, and CD34-positive cells. Podoplanin may therefore represent a sign of activation of a cohort of progenitor cells during different phases of post-ischemic myocardial wound repair. Podoplanin binds to C-type lectin-like receptor 2 (CLEC-2) which is exclusively expressed by platelets and a variety of immune cells. CLEC-2 is upregulated in CD11bhigh cells, including monocytes and macrophages, following inflammatory stimuli. We recently published that inhibition of the interaction between podoplanin-expressing cells and podoplanin-binding cells using podoplanin-neutralizing antibodies reduces but does not fully suppress inflammation post-MI while improving heart function and scar composition after ischemic injury. These data support an emerging and alternative mechanism of interactome in the heart that, when neutralized, leads to altered inflammatory response and preservation of cardiac function and structure. The overarching objective of this review is to assimilate and discuss the available evidence on the functional role of podoplanin-positive cells on cardiac fibrosis and remodeling. A detailed characterization of cell-to-cell interactions and paracrine signals between podoplanin-expressing cells and the other type of cells that compose the heart tissue is needed to open a new line of investigation extending beyond the known function of these cells. This review attempts to discuss the role and biology of podoplanin-positive cells in the context of cardiac injury, repair, and remodeling.
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Affiliation(s)
- Maria Cimini
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
| | - Raj Kishore
- Center for Translational Medicine, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, United States
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31
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Lam G, Zhou Y, Wang JX, Tsui YP. Targeting mesenchymal stem cell therapy for severe pneumonia patients. World J Stem Cells 2021; 13:139-154. [PMID: 33708343 PMCID: PMC7933990 DOI: 10.4252/wjsc.v13.i2.139] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2020] [Revised: 12/03/2020] [Accepted: 12/27/2020] [Indexed: 02/06/2023] Open
Abstract
Pneumonia is the inflammation of the lungs and it is the world's leading cause of death for children under 5 years of age. The latest coronavirus disease 2019 (COVID-19) virus is a prominent culprit to severe pneumonia. With the pandemic running rampant for the past year, more than 1590000 deaths has occurred worldwide up to December 2020 and are substantially attributable to severe pneumonia and induced cytokine storm. Effective therapeutic approaches in addition to the vaccines and drugs under development are hence greatly sought after. Therapies harnessing stem cells and their derivatives have been established by basic research for their versatile capacity to specifically inhibit inflammation due to pneumonia and prevent alveolar/pulmonary fibrosis while enhancing antibacterial/antiviral immunity, thus significantly alleviating the severe clinical conditions of pneumonia. In recent clinical trials, mesenchymal stem cells have shown effectiveness in reducing COVID-19-associated pneumonia morbidity and mortality; positioning these cells as worthy candidates for combating one of the greatest challenges of our time and shedding light on their prospects as a next-generation therapy to counter future challenges.
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Affiliation(s)
- Guy Lam
- School of Biomedical Sciences, University of Hong Kong, Hong Kong 999077, China
| | - Yuan Zhou
- Research and Development, Help Therapeutics Co. Ltd., Nanjing 211100, Jiangsu Province, China
| | - Jia-Xian Wang
- Research and Development, Help Therapeutics Co. Ltd., Nanjing 211100, Jiangsu Province, China
| | - Yat-Ping Tsui
- Research and Development, Help Therapeutics Co. Ltd., Nanjing 211100, Jiangsu Province, China.
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32
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Usunier B, Brossard C, L’Homme B, Linard C, Benderitter M, Milliat F, Chapel A. HGF and TSG-6 Released by Mesenchymal Stem Cells Attenuate Colon Radiation-Induced Fibrosis. Int J Mol Sci 2021; 22:ijms22041790. [PMID: 33670243 PMCID: PMC7916908 DOI: 10.3390/ijms22041790] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 01/27/2021] [Accepted: 02/05/2021] [Indexed: 12/18/2022] Open
Abstract
Fibrosis is a leading cause of death in occidental states. The increasing number of patients with fibrosis requires innovative approaches. Despite the proven beneficial effects of mesenchymal stem cell (MSC) therapy on fibrosis, there is little evidence of their anti-fibrotic effects in colorectal fibrosis. The ability of MSCs to reduce radiation-induced colorectal fibrosis has been studied in vivo in Sprague–Dawley rats. After local radiation exposure, rats were injected with MSCs before an initiation of fibrosis. MSCs mediated a downregulation of fibrogenesis by a control of extra cellular matrix (ECM) turnover. For a better understanding of the mechanisms, we used an in vitro model of irradiated cocultured colorectal fibrosis in the presence of human MSCs. Pro-fibrotic cells in the colon are mainly intestinal fibroblasts and smooth muscle cells. Intestinal fibroblasts and smooth muscle cells were irradiated and cocultured in the presence of unirradiated MSCs. MSCs mediated a decrease in profibrotic gene expression and proteins secretion. Silencing hepatocyte growth factor (HGF) and tumor necrosis factor-stimulated gene 6 (TSG-6) in MSCs confirmed the complementary effects of these two genes. HGF and TSG-6 limited the progression of fibrosis by reducing activation of the smooth muscle cells and myofibroblast. To settle in vivo the contribution of HGF and TSG-6 in MSC-antifibrotic effects, rats were treated with MSCs silenced for HGF or TSG-6. HGF and TSG-6 silencing in transplanted MSCs resulted in a significant increase in ECM deposition in colon. These results emphasize the potential of MSCs to influence the pathophysiology of fibrosis-related diseases, which represent a challenging area for innovative treatments.
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33
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Regenerative Medicine for Equine Musculoskeletal Diseases. Animals (Basel) 2021; 11:ani11010234. [PMID: 33477808 PMCID: PMC7832834 DOI: 10.3390/ani11010234] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 01/08/2021] [Accepted: 01/15/2021] [Indexed: 01/15/2023] Open
Abstract
Simple Summary Lameness due to musculoskeletal disease is the most common diagnosis in equine veterinary practice. Many of these orthopaedic disorders are chronic problems, for which no clinically satisfactory treatment exists. Thus, high hopes are pinned on regenerative medicine, which aims to replace or regenerate cells, tissues, or organs to restore or establish normal function. Some regenerative medicine therapies have already made their way into equine clinical practice mainly to treat tendon injures, tendinopathies, cartilage injuries and degenerative joint disorders with promising but diverse results. This review summarises the current knowledge of commonly used regenerative medicine treatments and critically discusses their use. Abstract Musculoskeletal injuries and chronic degenerative diseases commonly affect both athletic and sedentary horses and can entail the end of their athletic careers. The ensuing repair processes frequently do not yield fully functional regeneration of the injured tissues but biomechanically inferior scar or replacement tissue, causing high reinjury rates, degenerative disease progression and chronic morbidity. Regenerative medicine is an emerging, rapidly evolving branch of translational medicine that aims to replace or regenerate cells, tissues, or organs to restore or establish normal function. It includes tissue engineering but also cell-based and cell-free stimulation of endogenous self-repair mechanisms. Some regenerative medicine therapies have made their way into equine clinical practice mainly to treat tendon injures, tendinopathies, cartilage injuries and degenerative joint disorders with promising results. However, the qualitative and quantitative spatiotemporal requirements for specific bioactive factors to trigger tissue regeneration in the injury response are still unknown, and consequently, therapeutic approaches and treatment results are diverse. To exploit the full potential of this burgeoning field of medicine, further research will be required and is ongoing. This review summarises the current knowledge of commonly used regenerative medicine treatments in equine patients and critically discusses their use.
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Mahmood A, Seetharaman R, Kshatriya P, Patel D, Srivastava AS. Stem Cell Transplant for Advanced Stage Liver Disorders: Current Scenario and Future Prospects. Curr Med Chem 2021; 27:6276-6293. [PMID: 31584360 DOI: 10.2174/0929867326666191004161802] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 09/11/2019] [Accepted: 09/22/2019] [Indexed: 01/10/2023]
Abstract
BACKGROUND Chronic Liver Disorders (CLD), caused by the lifestyle patterns like alcoholism or by non-alcoholic fatty liver disease or because of virus-mediated hepatitis, affect a large population fraction across the world. CLD progresses into end-stage diseases with a high mortality rate. Liver transplant is the only approved treatment available for such end-stage disease patients. However, the number of liver transplants is limited due to the limited availability of suitable donors and the extremely high cost of performing the procedure. Under such circumstances, Stem Cell (SC) mediated liver regeneration has emerged as a potential therapeutic alternative approach. OBJECTIVE This review aims to critically analyze the current status and future prospects of stem cellbased interventions for end-stage liver diseases. The clinical studies undertaken, the mechanism underlying therapeutic effects and future directions have been examined. METHOD The clinical trial databases were searched at https://clinicaltrials.gov.in and http://www.isrctn.com to identify randomized, non-randomized and controlled studies undertaken with keywords such as "liver disorder and Mesenchymal Stem Cells (MSCs)", "liver cirrhosis and MSCs" and "liver disorder and SCs". Furthermore, https://www.ncbi.nlm.nih.gov/pubmed/ database was also explored with similar keywords for finding the available reports and their critical analyses. RESULTS The search results yielded a significant number of studies that used bone marrow-derived stem cells, MSCs and hepatocytes. The studies clearly indicated that SCs play a key role in the hepatoprotection process by some mechanisms involving anti-inflammation, auto-immune-suppression, angiogenesis and anti-apoptosis. Further, studies indicated that SCs derived paracrine factors promote angiogenesis, reduce inflammation and inhibit hepatocyte apoptosis. CONCLUSION The SC-based interventions provide a significant improvement in patients with CLD; however, there is a need for randomized, controlled studies with the analysis of a long-term follow-up.
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Affiliation(s)
| | | | | | | | - Anand S Srivastava
- Global Institute of Stem Cell Therapy and Research, 4660 La Jolla Village Drive, San Diego, CA 92122, United States
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Putra A, Alif I, Hamra N, Santosa O, Kustiyah AR, Muhar AM, Lukman K. MSC-released TGF-β regulate α-SMA expression of myofibroblast during wound healing. J Stem Cells Regen Med 2020; 16:73-79. [PMID: 33414583 DOI: 10.46582/jsrm.1602011] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2019] [Accepted: 10/14/2020] [Indexed: 12/27/2022]
Abstract
Objective: Wound healing without fibrosis remains a clinical challenge and a new strategy to promote the optimal wound healing is needed. Mesenchymal stem cells (MSCs) can completely regenerate tissue injury due to the robust MSCs ability in controlling inflammation niche leading to granulation tissue formation, particularly through a release of various growth factors including transforming growth factor-β (TGF-β). In response to TGF-β stimulation, fibroblasts differentiate into myofibroblast, marked by alpha-smooth muscle actin (α-SMA) that leads to wound healing acceleration. On the other hand, sustained activation of TGF-β in wound areas may contribute to fibrosis-associated scar formation. The aim of this study was to evaluate the α-SMA expression of myofibroblast induced by MSC-released TGF-β during wound healing process. Materials and Methods: Twenty-four full-thickness excisional rat wound models were randomly divided into four groups: sham (Sh), Control (C), and MSCs treatment groups; topically treated by the MSCs at doses 2x106 cells (T1) and 1x106 cells (T2), respectively. While the control group was treated with NaCl. TGF-β level was determined using ELISA assay, α-SMA expression of myofibroblast was analyzed by immunofluorescence staining, and wound size measurement was calculated using a standard caliper. Results: This study showed a significant increase in TGF-β levels in all treatment groups on days 3 and 6. This finding was consistent with a significant increase of α-SMA expression of myofibroblast at day 6 and wound closure percentage, indicating that MSCs might promote an increase of wound closure. Conclusion: MSCs regulated the release of TGF-β to induce α-SMA expression of myofibroblast for accelerating an optimal wound healing.
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Affiliation(s)
- Agung Putra
- Stem Cell And Cancer Research (SCCR), Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia.,Department of Postgraduate Biomedical Science, Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia.,Department of Pathological Anatomy, Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia
| | - Iffan Alif
- Stem Cell And Cancer Research (SCCR), Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia
| | - Nurfitriani Hamra
- Postgraduate Biomedical Student, Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia
| | - Octyana Santosa
- Medical Student, Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia
| | - Azizah Retno Kustiyah
- Department of Pediatric, Medical Faculty, Universitas Islam Sultan Agung (UNISSULA), Semarang, Central Java, Indonesia
| | - Adi Muradi Muhar
- Department of Surgery, Faculty of Medicine, Universitas Sumatera Utara (USU), Medan, Indonesia
| | - Kiki Lukman
- Department of Surgery, Faculty of Medicine, Universitas Padjadjaran (UNPAD), Bandung,West Java, Indonesia
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36
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Zhang N, Luo X, Zhang S, Liu R, Liang L, Su W, Liang D. Subconjunctival injection of tumor necrosis factor-α pre-stimulated bone marrow-derived mesenchymal stem cells enhances anti-inflammation and anti-fibrosis in ocular alkali burns. Graefes Arch Clin Exp Ophthalmol 2020; 259:929-940. [PMID: 33237391 DOI: 10.1007/s00417-020-05017-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/23/2020] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 02/06/2023] Open
Abstract
PURPOSE To investigate the therapeutic effect of subconjunctival injection of tumor necrosis factor-α (TNF-α) pre-stimulated bone marrow-derived mesenchymal stem cells (BMMSCs) on ocular alkali burns in a rat model. METHODS After applying a 6 mm filter paper soaking in 1 N NaOH on the cornea of rats, the suspension of TNF-α pre-stimulated BMMSCs, BMMSCs and PBS were given subconjunctivally and respectively. Corneal epithelial defect, corneal opacity, inflammation as well as PTGS2 and TSG-6 expression on day 7 and fibrosis on day 14 were compared. RESULTS TNF-α pre-stimulated BMMSCs group had a more predominate effect on promoting corneal epithelial repairing, decreasing corneal opacity, reducing inflammatory cells and CD68 + macrophages on day 7 and suppressing fibrosis on day 14 compared to BMMSCs group. Besides, it had significant increased expressions of PTGS2 and TSG-6 in vitro. Pre-treated with Indomethacin revealed a reverse effect on above-mentioned changes. CONCLUSION Subconjunctival injection of TNF-α pre-stimulated BMMSCs enhanced anti-inflammatory and anti-fibrotic effect in ocular alkali burns, which was possibly though up regulation of PTGS2 and TSG-6 expression.
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Affiliation(s)
- Nuan Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Xiaohui Luo
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Shiyao Zhang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Ren Liu
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China
| | - Lingyi Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China.
| | - Wenru Su
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China.
| | - Dan Liang
- State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, Guangzhou, 510060, China.
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Yang Y, Zhu S, Li Y, Lu Q, Zhang Q, Su L, Zhang Q, Zhao Y, Luo Y, Liu Y. Human umbilical cord mesenchymal stem cells ameliorate skin fibrosis development in a mouse model of bleomycin-induced systemic sclerosis. Exp Ther Med 2020; 20:257. [PMID: 33199983 PMCID: PMC7664606 DOI: 10.3892/etm.2020.9387] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2020] [Accepted: 09/22/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) infusion has become a novel therapeutic strategy for complex autoimmune diseases; however, few detailed studies have been performed to investigate the benefit and mechanism of MSC treatment on systemic sclerosis (SSc). The present study aimed to evaluate the therapeutic effect of human umbilical cord derived-MSCs (UC-MSCs) on bleomycin-induced SSc in mice and explore the potential underlying mechanism. The murine SSc model was established by daily subcutaneous injection of bleomycin for 4 weeks, followed with two UC-MSC infusions every 7 days. Skin fibrosis was assessed by H&E and Masson staining. Flow cytometry was used to determine IL-17A, IFN-γ, tumor necrosis factor-β, IL-10 and IL-12 levels in serum samples and T cell subsets in murine spleen. Additionally, gene expression levels of cytokines and fibrosis markers in skin samples were measured by reverse transcription-quantitative PCR. Immunofluorescence staining was performed to track UC-MSC localization and lymphocyte cell infiltration in vivo. UC-MSC treatment exerted an anti-fibrotic role in bleomycin-induced SSc mice, as confirmed by histological improvement, decreased collagen synthesis, and reduced collagen-1α1, collagen-1α2, fibronectin-1 and α-smooth muscle actin gene expression levels. The results indicated that UC-MSC treatment only had a limited systematic effect on cytokine production in serum samples and T cell activation in the spleen. By contrast, T helper (Th)17 cell infiltration and activation in skin were efficiently inhibited after UC-MSC infusion, as evidenced by the decreased IL-17A and retinoic acid-related orphan receptor γt gene expression as well as IL-17A production. UC-MSC administration significantly ameliorated bleomycin-induced skin fibrosis and collagen formation primarily by eliminating local inflammation and Th17 cell activation in the skin; however, the systemic inhibitory effect of UM-MSCs on cytokines was less profound.
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Affiliation(s)
- Yuan Yang
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China.,Department of Rheumatology and Immunology, The First Affiliated Hospital of Chengdu Medical College, Chengdu, Sichuan 610500, P.R. China
| | - Shuai Zhu
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yanhong Li
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qian Lu
- Department of Biomedical Engineering, College of Engineering and Applied Sciences, Nanjing University, Nanjing, Jiangsu 210023, P.R. China
| | - Qiuyi Zhang
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Linchong Su
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Qiuping Zhang
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yi Zhao
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yubin Luo
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
| | - Yi Liu
- Department of Rheumatology, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, P.R. China
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Hypothesizing the therapeutic potential of mesenchymal stem cells in oral submucous fibrosis. Med Hypotheses 2020; 144:110204. [PMID: 33254511 DOI: 10.1016/j.mehy.2020.110204] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2020] [Revised: 08/10/2020] [Accepted: 08/18/2020] [Indexed: 12/31/2022]
Abstract
Oral submucous fibrosis is the direct consequence of a sustained pro-inflammatory environment characterized by excessive collagen deposition causing tissue fibrosis, and progressive degeneration of vital structures including muscle. The pathogenesis of oral submucous fibrosis is largely mediated by the pro-inflammatory, pro-fibrotic cytokines, excessive oxidative stress, abnormal angiogenesis, and epithelial to mesenchymal transition. Mesenchymal stem cells largely known for their regenerative potential have shown to have an immunomodulatory, anti-fibrotic, anti-oxidative, and angiogenic potential. Thus, mesenchymal stem cells, when introduced in an oral submucous fibrosis micro-environment, could potentially counter the progressive fibrosis. The present hypotheses discuss the various pathogenic aspects of oral submucous fibrosis and the properties of mesenchymal stem cells which could aid in halting the disease progression.
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SIRT1-modified human umbilical cord mesenchymal stem cells ameliorate experimental peritoneal fibrosis by inhibiting the TGF-β/Smad3 pathway. Stem Cell Res Ther 2020; 11:362. [PMID: 32811535 PMCID: PMC7436980 DOI: 10.1186/s13287-020-01878-2] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 07/01/2020] [Accepted: 08/05/2020] [Indexed: 12/12/2022] Open
Abstract
Introduction Peritoneal fibrosis is a serious complication of long-term peritoneal dialysis (PD). Combination therapies are emerging as a promising treatment for tissue damage. Here, we investigated the therapeutic potential of SIRT1-modified human umbilical cord mesenchymal stem cells (hUCMSCs) for peritoneal fibrosis. Methods SIRT1 was overexpressed in hUCMSCs to establish SIRT1-modified hUCMSCs. Co-culture and transplantation experiments were performed in TGF-β-stimulated Met-5A cells and peritoneal damage rodent model to assess the therapeutic potential of SIRT1-modified hUCMSCs for peritoneal fibrosis through qPCR, Western blot, and peritoneal function analyses. Results SIRT1-modified hUCMSC administration had more potent anti-fibrosis ability than hUCMSCs, which significantly inhibited the expression of fibrotic genes and suppressed EMT process, increased ultrafiltration volume, and restored homeostasis of bioincompatible factors in dialysis solution. Mechanistically, SIRT1-modified hUCMSCs attenuated peritoneal fibrosis through reducing peritoneal inflammation and inhibiting the TGF-β/Smad3 pathway in peritoneal omentum tissues. Conclusion SIRT1-modified hUCMSCs might work as a promising therapeutic strategy for the treatment of peritoneal dialysis-induced peritoneal damage and fibrosis.
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Matz EL, Scarberry K, Terlecki R. Platelet-Rich Plasma and Cellular Therapies for Sexual Medicine and Beyond. Sex Med Rev 2020; 10:174-179. [PMID: 32800771 DOI: 10.1016/j.sxmr.2020.07.001] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 07/12/2020] [Accepted: 07/13/2020] [Indexed: 01/16/2023]
Abstract
INTRODUCTION Efforts to understand and unlock the body's potential for regeneration have increased dramatically in recent years. So-called "biohacking" hopes to improve functionality and reverse disease processes. OBJECTIVES This review will seek to summarize the available data for the use of platelet-rich plasma, cellular therapies, and other novel therapeutics within sexual medicine. METHODS The PubMed database search was performed using the keywords "Stem cell therapy in Erectile dysfunction (ED)", "Gene therapy in ED", "Novel therapeutics for ED", and "Biohacking". Popular news articles for regulation of stem cell therapy were reviewed. RESULTS Research efforts have managed to produce an array of novel therapeutics, including stem cell therapy and platelet-rich plasma. Although the use of these items has been largely focused within specialties other than urology, applications involving sexual medicine have been documented and appear to be increasing. CONCLUSION Despite evidence of these technologies being adopted within clinical practices as revenue-generators, quality data to support efficacy are quite limited. Matz EL, Scarberry K, Terlecki R, Platelet-Rich Plasma and Cellular Therapies for Sexual Medicine and Beyond. Sex Med Rev 2020;XX:XXX-XXX.
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Affiliation(s)
- Ethan L Matz
- Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Kyle Scarberry
- Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA
| | - Ryan Terlecki
- Department of Urology, Wake Forest School of Medicine, Winston-Salem, NC, USA.
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41
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Ahangar P, Mills SJ, Smith LE, Strudwick XL, Ting AE, Vaes B, Cowin AJ. Human multipotent adult progenitor cell-conditioned medium improves wound healing through modulating inflammation and angiogenesis in mice. Stem Cell Res Ther 2020; 11:299. [PMID: 32680566 PMCID: PMC7368692 DOI: 10.1186/s13287-020-01819-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 06/15/2020] [Accepted: 07/08/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Stem cell therapies have been widely investigated for their healing effects. However, the translation of these therapies has been hampered by the requirement to deliver live allogeneic or autologous cells directly to the wound in a clinical setting. Multipotent adult progenitor cells (MAPC® cells) are a subpopulation of bone marrow-derived adherent stem cells that secrete a wide range of factors known to accelerate the wound healing process. The aim of this study was to determine the impact of MAPC cells secretome on healing outcomes without the presence of MAPC cells. METHODS The effect of MAPC-conditioned medium (MAPC-CM) on the capacity of keratinocytes, fibroblasts and endothelial cells to migrate and proliferate was determined in vitro using scratch wound closure and WST1 assay, respectively. The effect of MAPC-CM on collagen deposition and angiogenesis was also assessed using in vitro methods. Additionally, two excisional wounds were created on the dorsal surface of mice (n = 8/group) and 100 μL of 20× MAPC-CM were intradermally injected to the wound margins. Wound tissues were collected at 3, 7 and 14 days post-wounding and stained with H&E for microscopic analysis. Immunohistochemistry was performed to investigate inflammation, angiogenesis and collagen deposition in the wounds. RESULTS Skin fibroblasts, keratinocytes and endothelial cells treated with MAPC-CM all showed improved rates of scratch closure and increased cellular proliferation. Moreover, fibroblasts treated with MAPC-CM deposited more collagens I and III and endothelial cells treated with MAPC-CM showed increased capillary tube formation. Murine excisional wounds intradermally injected with MAPC-CM showed a significant reduction in the wound area and an increase in the rate of reepithelialisation. The results also showed that inflammatory cell infiltration was decreased while an increase in angiogenesis, as well as collagens I and III expressions, was observed. CONCLUSION These findings suggest that factors produced by MAPC cells can have an important effect on cutaneous wound healing by affecting skin cell proliferation and migration, balancing inflammation and improving the formation of extracellular matrix and angiogenesis. Development of stem cell-free therapy for the treatment of wounds may be a more clinically translatable approach for improving healing outcomes.
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Affiliation(s)
- Parinaz Ahangar
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Stuart J Mills
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Louise E Smith
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia.,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia
| | - Xanthe L Strudwick
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia
| | | | - Bart Vaes
- ReGenesys BVBA, Bio-Incubator Leuven, Gaston Geenslaan 1, 3001, Heverlee, Belgium
| | - Allison J Cowin
- Future Industries Institute, University of South Australia, Adelaide, SA, 5000, Australia. .,Cell Therapy Manufacturing Cooperative Research Centre, Adelaide, SA, 5000, Australia.
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Dhall S, Lerch A, Johnson N, Jacob V, Jones B, Park MS, Sathyamoorthy M. A Flowable Placental Formulation Prevents Bleomycin-Induced Dermal Fibrosis in Aged Mice. Int J Mol Sci 2020; 21:E4242. [PMID: 32545915 PMCID: PMC7352837 DOI: 10.3390/ijms21124242] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/04/2020] [Accepted: 06/11/2020] [Indexed: 12/26/2022] Open
Abstract
Fibrosis, the thickening and scarring of injured connective tissue, leads to a loss of organ function. Multiple cell types, including T-cells, macrophages, fibrocytes, and fibroblasts/myofibroblasts contribute to scar formation via secretion of inflammatory factors. This event results in an increase in oxidative stress and deposition of excessive extracellular matrix (ECM), characteristic of fibrosis. Further, aging is known to predispose connective tissue to fibrosis due to reduced tissue regeneration. In this study, we investigated the anti-fibrotic activity of a flowable placental formulation (FPF) using a bleomycin-induced dermal fibrosis model in aged mice. FPF consisted of placental amnion/chorion- and umbilical tissue-derived ECM and cells. The mice were injected with either FPF or PBS, followed by multiple doses of bleomycin. Histological assessment of FPF-treated skin samples revealed reduced dermal fibrosis, inflammation, and TGF-β signaling compared to the control group. Quantitative RT-PCR and Next Generation Sequencing analysis of miRNAs further confirmed anti-fibrotic changes in the FPF-treated group at both the gene and transcriptional levels. The observed modulation in miRNAs was associated with inflammation, TGF-β signaling, fibroblast proliferation, epithelial-mesenchymal transition and ECM deposition. These results demonstrate the potential of FPF in preventing fibrosis and may be of therapeutic benefit for those at higher risk of fibrosis due to wounds, aging, exposure to radiation and genetic predisposition.
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Affiliation(s)
- Sandeep Dhall
- Smith & Nephew Plc., Columbia, MD 21046, USA; (A.L.); (N.J.); (V.J.); (B.J.); (M.S.P.)
| | | | | | | | | | | | - Malathi Sathyamoorthy
- Smith & Nephew Plc., Columbia, MD 21046, USA; (A.L.); (N.J.); (V.J.); (B.J.); (M.S.P.)
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Rostom DM, Attia N, Khalifa HM, Abou Nazel MW, El Sabaawy EA. The Therapeutic Potential of Extracellular Vesicles Versus Mesenchymal Stem Cells in Liver Damage. Tissue Eng Regen Med 2020; 17:537-552. [PMID: 32506351 DOI: 10.1007/s13770-020-00267-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2020] [Revised: 04/05/2020] [Accepted: 04/15/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The extracellular vesicles (EVs) secreted by bone marrow-derived mesenchymal stem cells (MSCs) hold significant potential as a novel alternative to whole-cell therapy. We herein compare the therapeutic potential of BM-MSCs versus their EVs (MSC-EVs) in an experimental Carbon tetrachloride (CCl4)-induced liver damage rat model. METHODS Rats with liver damage received a single IV injection of MSC-EVs, 1 million MSCs, or 3 million MSCs. The therapeutic efficacy of each treatment was assessed using liver histopathology, liver function tests and immunohistochemistry for liver fibrosis and hepatocellular injury. RESULTS Animals that received an injection of either MSCs-EVs or 3 million MSCs depicted significant regression of collagen deposition in the liver tissue and marked attenuation of hepatocellular damage, both structurally and functionally. CONCLUSION Similar to high doses of MSC-based therapy (3 million MSCs), MSC-EVs mitigated the fibrogenesis and hepatocellular injury in a rat model of CCl4-induced liver fibrosis. The anti-fibrinogenic effect was induced by attenuating hepatic stellate cell activation. Therefore, the administration of MSC-EVs could be considered as a candidate cell-free therapeutic strategy for liver fibrosis and hepatocellular damage.
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Affiliation(s)
- Dina M Rostom
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Noha Attia
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt. .,Department of Basic Sciences, The American University of Antigua - College of Medicine, University Park, Jabberwock Beach Road, P.O. Box 1451, Coolidge, Antigua and Barbuda.
| | - Hoda M Khalifa
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Maha W Abou Nazel
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
| | - Eshrak A El Sabaawy
- Department of Medical Histology and Cell Biology, Faculty of Medicine, University of Alexandria, Dr. Fahmi Abdelmeguid St., Mowassah Campus, Alexandria, 21561, Egypt
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Tracy E, Rowe G, LeBlanc AJ. Cardiac tissue remodeling in healthy aging: the road to pathology. Am J Physiol Cell Physiol 2020; 319:C166-C182. [PMID: 32432929 DOI: 10.1152/ajpcell.00021.2020] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
This review aims to highlight the normal physiological remodeling that occurs in healthy aging hearts, including changes that occur in contractility, conduction, valve function, large and small coronary vessels, and the extracellular matrix. These "normal" age-related changes serve as the foundation that supports decreased plasticity and limited ability for tissue remodeling during pathophysiological states such as myocardial ischemia and heart failure. This review will identify populations at greater risk for poor tissue remodeling in advanced age along with present and future therapeutic strategies that may ameliorate dysfunctional tissue remodeling in aging hearts.
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Affiliation(s)
- Evan Tracy
- Department of Physiology, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky
| | - Gabrielle Rowe
- Department of Physiology, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky
| | - Amanda J LeBlanc
- Department of Physiology, Cardiovascular Innovation Institute, University of Louisville, Louisville, Kentucky
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Basalova N, Sagaradze G, Arbatskiy M, Evtushenko E, Kulebyakin K, Grigorieva O, Akopyan Z, Kalinina N, Efimenko A. Secretome of Mesenchymal Stromal Cells Prevents Myofibroblasts Differentiation by Transferring Fibrosis-Associated microRNAs within Extracellular Vesicles. Cells 2020; 9:cells9051272. [PMID: 32443855 PMCID: PMC7290371 DOI: 10.3390/cells9051272] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2020] [Revised: 05/11/2020] [Accepted: 05/14/2020] [Indexed: 12/20/2022] Open
Abstract
Fibroblasts differentiation into myofibroblasts is a central event of tissue fibrosis. Multipotent mesenchymal stromal cells (MSCs) secretome can interfere with fibrosis development; despite precise underlying mechanisms remain unclear. In this study, we tested the hypothesis that MSC secretome can affect fibroblast’ differentiation into myofibroblasts by delivering regulatory RNAs, including microRNAs to these cells. Using the model of transforming growth factor-beta (TGFbeta)-induced fibroblast differentiation into myofibroblasts, we tested the activity of human MSC secretome components, specifically extracellular vesicles (MSC-EV). We showed that MSC-EV down-regulated secretion of extracellular matrix proteins by fibroblasts as well as suppressed their contractility resulting in prevention as well as reversion of fibroblasts differentiation to myofibroblasts. High-throughput sequencing of RNAs extracted from MSC-EV has revealed many fibrosis-associated microRNAs. Fibroblast treatment with MSC-EV led to direct transfer of microRNAs, which resulted in the elevation of most prominent fibrosis-associated microRNAs, including microRNA-21 and microRNA-29c. Using MSC-EV transfection by antagomirs to these microRNAs we demonstrated their involvement in the suppression of fibroblast differentiation in our model. Taken together, MSC secretome can suppress fibrosis by prevention of fibroblast differentiation into myofibroblasts as well as induce de-differentiation of the latter by direct transfer of specific microRNAs.
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Affiliation(s)
- Nataliya Basalova
- Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University, 119192 Moscow, Russia; (N.B.); (G.S.); (O.G.); (Z.A.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (M.A.); (K.K.); (N.K.)
| | - Georgy Sagaradze
- Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University, 119192 Moscow, Russia; (N.B.); (G.S.); (O.G.); (Z.A.)
| | - Mikhail Arbatskiy
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (M.A.); (K.K.); (N.K.)
| | - Evgeniy Evtushenko
- Faculty of Chemistry, Lomonosov Moscow State University, 119991 Moscow, Russia;
| | - Konstantin Kulebyakin
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (M.A.); (K.K.); (N.K.)
| | - Olga Grigorieva
- Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University, 119192 Moscow, Russia; (N.B.); (G.S.); (O.G.); (Z.A.)
| | - Zhanna Akopyan
- Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University, 119192 Moscow, Russia; (N.B.); (G.S.); (O.G.); (Z.A.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (M.A.); (K.K.); (N.K.)
| | - Natalia Kalinina
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (M.A.); (K.K.); (N.K.)
| | - Anastasia Efimenko
- Institute for Regenerative Medicine, Medical Research and Educational Centre, Lomonosov Moscow State University, 119192 Moscow, Russia; (N.B.); (G.S.); (O.G.); (Z.A.)
- Faculty of Medicine, Lomonosov Moscow State University, 119192 Moscow, Russia; (M.A.); (K.K.); (N.K.)
- Correspondence:
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Rogers CJ, Harman RJ, Bunnell BA, Schreiber MA, Xiang C, Wang FS, Santidrian AF, Minev BR. Rationale for the clinical use of adipose-derived mesenchymal stem cells for COVID-19 patients. J Transl Med 2020; 18:203. [PMID: 32423449 PMCID: PMC7232924 DOI: 10.1186/s12967-020-02380-2] [Citation(s) in RCA: 75] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2020] [Accepted: 05/14/2020] [Indexed: 02/08/2023] Open
Abstract
In late 2019, a novel coronavirus (SARS-CoV-2) emerged in Wuhan, capital city of Hubei province in China. Cases of SARS-CoV-2 infection quickly grew by several thousand per day. Less than 100 days later, the World Health Organization declared that the rapidly spreading viral outbreak had become a global pandemic. Coronavirus disease 2019 (COVID-19) is typically associated with fever and respiratory symptoms. It often progresses to severe respiratory distress and multi-organ failure which carry a high mortality rate. Older patients or those with medical comorbidities are at greater risk for severe disease. Inflammation, pulmonary edema and an over-reactive immune response can lead to hypoxia, respiratory distress and lung damage. Mesenchymal stromal/stem cells (MSCs) possess potent and broad-ranging immunomodulatory activities. Multiple in vivo studies in animal models and ex vivo human lung models have demonstrated the MSC's impressive capacity to inhibit lung damage, reduce inflammation, dampen immune responses and aid with alveolar fluid clearance. Additionally, MSCs produce molecules that are antimicrobial and reduce pain. Upon administration by the intravenous route, the cells travel directly to the lungs where the majority are sequestered, a great benefit for the treatment of pulmonary disease. The in vivo safety of local and intravenous administration of MSCs has been demonstrated in multiple human clinical trials, including studies of acute respiratory distress syndrome (ARDS). Recently, the application of MSCs in the context of ongoing COVID-19 disease and other viral respiratory illnesses has demonstrated reduced patient mortality and, in some cases, improved long-term pulmonary function. Adipose-derived stem cells (ASC), an abundant type of MSC, are proposed as a therapeutic option for the treatment of COVID-19 in order to reduce morbidity and mortality. Additionally, when proven to be safe and effective, ASC treatments may reduce the demand on critical hospital resources. The ongoing COVID-19 outbreak has resulted in significant healthcare and socioeconomic burdens across the globe. There is a desperate need for safe and effective treatments. Cellular based therapies hold great promise for the treatment of COVID-19. This literature summary reviews the scientific rationale and need for clinical studies of adipose-derived stem cells and other types of mesenchymal stem cells in the treatment of patients who suffer with COVID-19.
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Affiliation(s)
| | | | - Bruce A. Bunnell
- Center for Stem Cell Research and Regenerative Medicine, Tulane University School of Medicine, New Orleans, LA USA
| | - Martin A. Schreiber
- Department of Surgery, Oregon Health and Science University, Portland, OR USA
| | - Charlie Xiang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, 310003 China
| | - Fu-Sheng Wang
- Treatment and Research Center for Infectious Diseases, The Fifth Medical Center, Beijing, 100039 China
| | | | - Boris R. Minev
- Calidi Biotherapeutics, Inc., San Diego, CA USA
- Department of Radiation Medicine and Applied Sciences, Moores UCSD Cancer Center, San Diego, CA USA
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Khalifa YH, Mourad GM, Stephanos WM, Omar SA, Mehanna RA. Bone Marrow-Derived Mesenchymal Stem Cell Potential Regression of Dysplasia Associating Experimental Liver Fibrosis in Albino Rats. BIOMED RESEARCH INTERNATIONAL 2019; 2019:5376165. [PMID: 31781620 PMCID: PMC6874956 DOI: 10.1155/2019/5376165] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/21/2019] [Revised: 09/25/2019] [Accepted: 10/08/2019] [Indexed: 02/07/2023]
Abstract
OBJECTIVES Assessing the therapeutic efficacy of superparamagnetic iron oxide nanoparticles (SPIO) labeled bone marrow-derived mesenchymal stem cells (BM-MSCs) on experimental liver fibrosis and associated dysplasia. MATERIALS AND METHODS MSCs were obtained from 10 male Sprague-Dawley rats while 50 female rats were divided into control (CG), liver fibrosis (CCL4, intraperitoneal injection of CCl4 for 8 weeks), and CCL4 rats treated with SPIO-labeled MSCs (MSCs/CCl4) with and without continuing CCL4 injection for another 8 weeks. Assessment included liver histopathology, liver function tests, transmission electron microscopic tracing for homing of SPIO-MSCs, immunofluorescence histochemistry for fibrosis and dysplasia markers (transforming growth factor-beta (TGF-β1), proliferation nuclear antigen (PCNA), glypican 3)), and quantitative gene expression analysis for matrix metalloproteinase-1 (MMP-1) and tissue inhibitor of metalloproteinase-1 (TIMP-1). RESULTS SPIO-labeled MSCs were engrafted in the fibrotic liver and the BM/MSCs demonstrated regression for fibrous tissue deposition and inhibition progression of dysplastic changes in the liver of CCl4-treated rats on both the histological and molecular levels. CONCLUSION BM-MSCs possess regenerative and antidysplastic potentials.
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Affiliation(s)
- Yasmine H. Khalifa
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
| | - Ghada M. Mourad
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
- Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21514, Egypt
| | - Wahid M. Stephanos
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
| | - Sahar A. Omar
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
| | - Radwa A. Mehanna
- Center of Excellence for Research in Regenerative Medicine and Applications (CERRMA), Faculty of Medicine, Alexandria University, Alexandria 21514, Egypt
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Dr. Fahmi Abdel Meguid Street, Mowassat Building, El Shatby, Alexandria 21561, Egypt
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Omar AM, Meleis AE, Arfa SA, Zahran NM, Mehanna RA. Comparative Study of the Therapeutic Potential of Mesenchymal Stem Cells Derived from Adipose Tissue and Bone Marrow on Acute Myocardial Infarction Model. Oman Med J 2019; 34:534-543. [PMID: 31745418 PMCID: PMC6851069 DOI: 10.5001/omj.2019.97] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2019] [Accepted: 02/24/2019] [Indexed: 02/05/2023] Open
Abstract
OBJECTIVES Stem cell therapy is a promising approach in the treatment of acute myocardial infarction (AMI). Mesenchymal stem cells (MSC) from bone marrow (BM-MSC) and adipose tissue (AT-MSC) are attractive and feasible for preclinical and clinical trials. In this study, we compared the therapeutic potential of BM-MSC and AT-MSC in repairing the hearts of rats with isoproterenol (ISO)-induced AMI. METHODS Forty-two female rats were assigned into two groups; the optimization and the experimental group. The optimization groups were further subdivided into control group and the AMI induced group (using ISO). The experimental group was subdivided into AMI+cell-free media injected in the tail vein, AMI+BM-MSC, and AMI+AT-MSC groups treated with the intravenous injection of their respective cell types. Twenty-eight days after induction, electrocardiogram (ECG) was performed, and heart tissue samples were collected for histological assessment and cells tracing. RESULTS MSC therapy repaired cardiac functions shown by the restoration of ST segment, QT and QRS intervals in the ECG when compared to the AMI group. Infarct area was significantly decreased, and cardiac tissue regeneration signs were shown on histopathological examination. CONCLUSIONS Both MSC sources proved to be equally efficient in the assessed parameters.
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Affiliation(s)
- Amira M. Omar
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Anisa E. Meleis
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Samia A. Arfa
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Noha M. Zahran
- Histology and Cell Biology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
| | - Radwa A. Mehanna
- Medical Physiology Department, Faculty of Medicine, Alexandria University, Alexandria, Egypt
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria, Egypt
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Mesenchymal stem cells preserve their stem cell traits after exposure to antimetabolite chemotherapy. Stem Cell Res 2019; 40:101536. [PMID: 31437767 DOI: 10.1016/j.scr.2019.101536] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2019] [Revised: 06/29/2019] [Accepted: 08/12/2019] [Indexed: 12/14/2022] Open
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Choi YJ, Koo JB, Kim HY, Seo JW, Lee EJ, Kim WR, Cho JY, Hahm KB, Hong SP, Kim DH, Yoo JH. Umbilical cord/placenta-derived mesenchymal stem cells inhibit fibrogenic activation in human intestinal myofibroblasts via inhibition of myocardin-related transcription factor A. Stem Cell Res Ther 2019; 10:291. [PMID: 31547873 PMCID: PMC6757442 DOI: 10.1186/s13287-019-1385-8] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2019] [Revised: 08/14/2019] [Accepted: 08/15/2019] [Indexed: 12/22/2022] Open
Abstract
Background The lack of anti-fibrotic agents targeting intestinal fibrosis is a large unmet need in inflammatory bowel diseases, including Crohn’s disease and ulcerative colitis. Previous studies have found that perinatal tissue (umbilical cord, UC; placenta, PL)-derived mesenchymal stem cells (MSCs) reduce fibrosis in several organs. However, their effects on human intestinal fibrosis are poorly understood. This study investigated the anti-fibrogenic properties and mechanisms of MSCs derived from UC and PL (UC/PL-MSCs) on human primary intestinal myofibroblasts (HIMFs). Methods The HIMFs were treated with TGF-β1 and co-cultured with UC/PL-MSCs. We used a small molecular inhibitor CCG-100602 to examine whether serum response factor (SRF) and its transcriptional cofactor myocardin-related transcription factor A (MRTF-A) are involved in TGF-β1-induced fibrogenic activation in HIMFs. The anti-fibrogenic mechanism of UC/PL-MSCs on HIMFs was analyzed by detecting the expression of RhoA, MRTF-A, and SRF in HIMFs. Results UC/PL-MSCs reduced TGF-β1-induced procollagen1A1, fibronectin, and α-smooth muscle actin expression in HIMFs. This anti-fibrogenic effect was more apparent in the UC-MSCs. TGF-β1 stimulation increased the expressions of RhoA, MRTF-A, and SRF in the HIMFs. TGF-β1 induced the synthesis of procollagen1A1, fibronectin, and α-smooth muscle actin through a MRTF-A/SRF-dependent mechanism. Co-culture with the UC/PL-MSCs downregulated fibrogenesis by inhibition of RhoA, MRTF-A, and SRF expression. Conclusions UC/PL-MSCs suppress TGF-β1-induced fibrogenic activation in HIMFs by blocking the Rho/MRTF/SRF pathway and could be considered as a novel candidate for stem cell-based therapy of intestinal fibrosis. Electronic supplementary material The online version of this article (10.1186/s13287-019-1385-8) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Yoon Jeong Choi
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.,Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea
| | - Jun Bon Koo
- Clinical Research Center, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | | | - Jin Won Seo
- CHA Biotech, Co. Ltd., Seongnam, South Korea
| | | | - Woo Ram Kim
- Department of Surgery, CHA Bundang Medical Center, CHA University, Seongnam, South Korea
| | - Joo Young Cho
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Ki Baik Hahm
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Sung Pyo Hong
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea
| | - Duk Hwan Kim
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea.
| | - Jun-Hwan Yoo
- Digestive Disease Center, CHA Bundang Medical Center, CHA University, 59 Yatap-ro, Bundang-gu, Seongnam, 463-712, South Korea. .,Institute of Basic Medical Sciences, School of Medicine, CHA University, Seongnam, South Korea.
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