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1
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AlOraibi S, Taurin S, Alshammary S. Advancements in Umbilical Cord Biobanking: A Comprehensive Review of Current Trends and Future Prospects. Stem Cells Cloning 2024; 17:41-58. [PMID: 39655226 PMCID: PMC11626973 DOI: 10.2147/sccaa.s481072] [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: 06/02/2024] [Accepted: 11/01/2024] [Indexed: 12/12/2024] Open
Abstract
Biobanking has emerged as a transformative concept in advancing the medical field, particularly with the exponential growth of umbilical cord (UC) biobanking in recent decades. UC blood and tissue provide a rich source of primitive hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) for clinical transplantation, offering distinct advantages over alternative adult stem cell sources. However, to fully realize the therapeutic potential of UC-derived stem cells and establish a comprehensive global UC-biobanking network, it is imperative to optimize and standardize UC processing, cryopreservation methods, quality control protocols, and regulatory frameworks, alongside developing effective consent provisions. This review aims to comprehensively explore recent advancements in UC biobanking, focusing on the establishment of rigorous safety and quality control procedures, the standardization of biobanking operations, and the optimization and automation of UC processing and cryopreservation techniques. Additionally, the review examines the expanded clinical applications of UC stem cells, addresses the challenges associated with umbilical cord biobanking and UC-derived stem cell therapies, and discusses the promising role of artificial intelligence (AI) in enhancing various operational aspects of biobanking, streamlining data processing, and improving data analysis accuracy while ensuring compliance with safety and quality standards. By addressing these critical areas, this review seeks to provide insights into the future direction of UC biobanking and its potential to significantly impact regenerative medicine.
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Affiliation(s)
- Sahar AlOraibi
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sebastien Taurin
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
| | - Sfoug Alshammary
- Molecular Medicine Department, Princess Al Jawhara Center for Molecular Medicine, Genetics, and Hereditary Diseases, College of Medicine and Health Sciences, Arabian Gulf University, Manama, Bahrain
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2
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Abouzid MR, Umer AM, Jha SK, Akbar UA, Khraisat O, Saleh A, Mohamed K, Esteghamati S, Kamel I. Stem Cell Therapy for Myocardial Infarction and Heart Failure: A Comprehensive Systematic Review and Critical Analysis. Cureus 2024; 16:e59474. [PMID: 38832190 PMCID: PMC11145929 DOI: 10.7759/cureus.59474] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/07/2024] [Indexed: 06/05/2024] Open
Abstract
In exploring therapeutic options for ischemic heart disease (IHD) and heart failure, cell-based cardiac repair has gained prominence. This systematic review delves into the current state of knowledge surrounding cell-based therapies for cardiac repair. Employing a comprehensive search across relevant databases, the study identifies 35 included studies with diverse cell types and methodologies. Encouragingly, these findings reveal the promise of cell-based therapies in cardiac repair, demonstrating significant enhancements in left ventricular ejection fraction (LVEF) across the studies. Mechanisms of action involve growth factors that stimulate angiogenesis, differentiation, and the survival of transplanted cells. Despite these positive outcomes, challenges persist, including low engraftment rates, limitations in cell differentiation, and variations in clinical reproducibility. The optimal dosage and frequency of cell administration remain subjects of debate, with potential benefits from repeated dosing. Additionally, the choice between autologous and allogeneic stem cell transplantation poses a critical decision. This systematic review underscores the potential of cell-based therapies for cardiac repair, bearing implications for innovative treatments in heart diseases. However, further research is imperative to optimize cell type selection, delivery techniques, and long-term efficacy, fostering a more comprehensive understanding of cell-based cardiac repair.
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Affiliation(s)
- Mohamed R Abouzid
- Internal Medicine, Baptist Hospitals of Southeast Texas, Beaumont, USA
| | - Ahmed Muaaz Umer
- Internal Medicine Residency, Camden Clark Medical Center, Parkersburg, USA
| | - Suman Kumar Jha
- Internal Medicine, Sheer Memorial Adventist Hospital, Banepa, NPL
| | - Usman A Akbar
- Internal Medicine, Camden Clark Medical Center, Parkersburg, USA
| | - Own Khraisat
- Internal Medicine, King Hussein Medical City, Amman, JOR
| | - Amr Saleh
- Cardiovascular Medicine, Yale School of Medicine, New Haven, USA
| | - Kareem Mohamed
- Internal Medicine, University of Missouri Kansas City, Kansas City, USA
| | | | - Ibrahim Kamel
- Internal Medicine, Steward Carney Hospital, Boston, USA
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3
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Barrère-Lemaire S, Vincent A, Jorgensen C, Piot C, Nargeot J, Djouad F. Mesenchymal stromal cells for improvement of cardiac function following acute myocardial infarction: a matter of timing. Physiol Rev 2024; 104:659-725. [PMID: 37589393 DOI: 10.1152/physrev.00009.2023] [Citation(s) in RCA: 29] [Impact Index Per Article: 29.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Revised: 07/05/2023] [Accepted: 08/16/2023] [Indexed: 08/18/2023] Open
Abstract
Acute myocardial infarction (AMI) is the leading cause of cardiovascular death and remains the most common cause of heart failure. Reopening of the occluded artery, i.e., reperfusion, is the only way to save the myocardium. However, the expected benefits of reducing infarct size are disappointing due to the reperfusion paradox, which also induces specific cell death. These ischemia-reperfusion (I/R) lesions can account for up to 50% of final infarct size, a major determinant for both mortality and the risk of heart failure (morbidity). In this review, we provide a detailed description of the cell death and inflammation mechanisms as features of I/R injury and cardioprotective strategies such as ischemic postconditioning as well as their underlying mechanisms. Due to their biological properties, the use of mesenchymal stromal/stem cells (MSCs) has been considered a potential therapeutic approach in AMI. Despite promising results and evidence of safety in preclinical studies using MSCs, the effects reported in clinical trials are not conclusive and even inconsistent. These discrepancies were attributed to many parameters such as donor age, in vitro culture, and storage time as well as injection time window after AMI, which alter MSC therapeutic properties. In the context of AMI, future directions will be to generate MSCs with enhanced properties to limit cell death in myocardial tissue and thereby reduce infarct size and improve the healing phase to increase postinfarct myocardial performance.
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Affiliation(s)
- Stéphanie Barrère-Lemaire
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Christian Jorgensen
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | - Christophe Piot
- Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joël Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, Centre National de la Recherche Scientifique, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- LabEx Ion Channel Science and Therapeutics, Université de Nice, Nice, France
| | - Farida Djouad
- Institute of Regenerative Medicine and Biotherapies, Université de Montpellier, Institut National de la Santé et de la Recherche Médicale, Montpellier, France
- Centre Hospitalier Universitaire Montpellier, Montpellier, France
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Wang X, Yang C, Ma X, Li X, Qi Y, Bai Z, Xu Y, Ma K, Luo Y, Song J, Jia W, He Z, Liu Z. A division-of-labor mode contributes to the cardioprotective potential of mesenchymal stem/stromal cells in heart failure post myocardial infarction. Front Immunol 2024; 15:1363517. [PMID: 38562923 PMCID: PMC10982400 DOI: 10.3389/fimmu.2024.1363517] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Accepted: 03/04/2024] [Indexed: 04/04/2024] Open
Abstract
Background Treatment of heart failure post myocardial infarction (post-MI HF) with mesenchymal stem/stromal cells (MSCs) holds great promise. Nevertheless, 2-dimensional (2D) GMP-grade MSCs from different labs and donor sources have different therapeutic efficacy and still in a low yield. Therefore, it is crucial to increase the production and find novel ways to assess the therapeutic efficacy of MSCs. Materials and methods hUC-MSCs were cultured in 3-dimensional (3D) expansion system for obtaining enough cells for clinical use, named as 3D MSCs. A post-MI HF mouse model was employed to conduct in vivo and in vitro experiments. Single-cell and bulk RNA-seq analyses were performed on 3D MSCs. A total of 125 combination algorithms were leveraged to screen for core ligand genes. Shinyapp and shinycell workflows were used for deploying web-server. Result 3D GMP-grade MSCs can significantly and stably reduce the extent of post-MI HF. To understand the stable potential cardioprotective mechanism, scRNA-seq revealed the heterogeneity and division-of-labor mode of 3D MSCs at the cellular level. Specifically, scissor phenotypic analysis identified a reported wound-healing CD142+ MSCs subpopulation that is also associated with cardiac protection ability and CD142- MSCs that is in proliferative state, contributing to the cardioprotective function and self-renewal, respectively. Differential expression analysis was conducted on CD142+ MSCs and CD142- MSCs and the differentially expressed ligand-related model was achieved by employing 125 combination algorithms. The present study developed a machine learning predictive model based on 13 ligands. Further analysis using CellChat demonstrated that CD142+ MSCs have a stronger secretion capacity compared to CD142- MSCs and Flow cytometry sorting of the CD142+ MSCs and qRT-PCR validation confirmed the significant upregulation of these 13 ligand factors in CD142+ MSCs. Conclusion Clinical GMP-grade 3D MSCs could serve as a stable cardioprotective cell product. Using scissor analysis on scRNA-seq data, we have clarified the potential functional and proliferative subpopulation, which cooperatively contributed to self-renewal and functional maintenance for 3D MSCs, named as "division of labor" mode of MSCs. Moreover, a ligand model was robustly developed for predicting the secretory efficacy of MSCs. A user-friendly web-server and a predictive model were constructed and available (https://wangxc.shinyapps.io/3D_MSCs/).
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Affiliation(s)
- Xicheng Wang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Chao Yang
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Xiaoxue Ma
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Xiuhua Li
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Yiyao Qi
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhihui Bai
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Ying Xu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Keming Ma
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Yi Luo
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Jiyang Song
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Wenwen Jia
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
| | - Zhongmin Liu
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, School of Medicine, Tongji University, Shanghai, China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, China
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5
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Tang XL, Nasr M, Zheng S, Zoubul T, Stephan JK, Uchida S, Singhal R, Khan A, Gumpert A, Bolli R, Wysoczynski M. Bone Marrow and Wharton's Jelly Mesenchymal Stromal Cells are Ineffective for Myocardial Repair in an Immunodeficient Rat Model of Chronic Ischemic Cardiomyopathy. Stem Cell Rev Rep 2023; 19:2429-2446. [PMID: 37500831 PMCID: PMC10579184 DOI: 10.1007/s12015-023-10590-6] [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] [Accepted: 07/09/2023] [Indexed: 07/29/2023]
Abstract
BACKGROUND Although cell therapy provides benefits for outcomes of heart failure, the most optimal cell type to be used clinically remains unknown. Most of the cell products used for therapy in humans require in vitro expansion to obtain a suitable number of cells for treatment; however, the clinical background of the donor and limited starting material may result in the impaired proliferative and reparative capacity of the cells expanded in vitro. Wharton's jelly mesenchymal cells (WJ MSCs) provide a multitude of advantages over adult tissue-derived cell products for therapy. These include large starting tissue material, superior proliferative capacity, and disease-free donors. Thus, WJ MSC if effective would be the most optimal cell source for clinical use. OBJECTIVES This study evaluated the therapeutic efficacy of Wharton's jelly (WJ) and bone marrow (BM) mesenchymal stromal cells (MSCs) in chronic ischemic cardiomyopathy in rats. METHODS Human WJ MSCs and BM MSCs were expanded in vitro, characterized, and evaluated for therapeutic efficacy in a immunodeficient rat model of ischemic cardiomyopathy. Cardiac function was evaluated with hemodynamics and echocardiography. The extent of cardiac fibrosis, hypertrophy, and inflammation was assessed with histological analysis. RESULTS In vitro analysis revealed that WJ MSCs and BM MSCs are morphologically and immunophenotypically indistinguishable. Nevertheless, the functional analysis showed that WJ MSCs have a superior proliferative capacity, less senescent phenotype, and distinct transcriptomic profile compared to BM MSC. WJ MSCs and BM MSC injected in rat hearts chronically after MI produced a small, but not significant improvement in heart structure and function. Histological analysis showed no difference in the scar size, collagen content, cardiomyocyte cross-sectional area, and immune cell count. CONCLUSIONS Human WJ and BM MSC have a small but not significant effect on cardiac structure and function when injected intramyocardially in immunodeficient rats chronically after MI.
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Affiliation(s)
- Xian-Liang Tang
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marjan Nasr
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Shirong Zheng
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Taylor Zoubul
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Jonah K Stephan
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Shizuka Uchida
- Center for RNA Medicine, Department of Clinical Medicine, Aalborg University, Copenhagen, Denmark
| | - Richa Singhal
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Anna Gumpert
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Roberto Bolli
- Institute of Molecular Cardiology, University of Louisville School of Medicine, Louisville, KY, USA
| | - Marcin Wysoczynski
- Center for Cardiometabolic Science, University of Louisville School of Medicine, 580 South Preston St. - Rm 204B, Louisville, KY, 40202, USA.
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6
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Szydlak R. Mesenchymal stem cells in ischemic tissue regeneration. World J Stem Cells 2023; 15:16-30. [PMID: 36909782 PMCID: PMC9993139 DOI: 10.4252/wjsc.v15.i2.16] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Revised: 11/10/2022] [Accepted: 01/19/2023] [Indexed: 02/21/2023] Open
Abstract
Diseases caused by ischemia are one of the leading causes of death in the world. Current therapies for treating acute myocardial infarction, ischemic stroke, and critical limb ischemia do not complete recovery. Regenerative therapies opens new therapeutic strategy in the treatment of ischemic disorders. Mesenchymal stem cells (MSCs) are the most promising option in the field of cell-based therapies, due to their secretory and immunomodulatory abilities, that contribute to ease inflammation and promote the regeneration of damaged tissues. This review presents the current knowledge of the mechanisms of action of MSCs and their therapeutic effects in the treatment of ischemic diseases, described on the basis of data from in vitro experiments and preclinical animal studies, and also summarize the effects of using these cells in clinical trial settings. Since the obtained therapeutic benefits are not always satisfactory, approaches aimed at enhancing the effect of MSCs in regenerative therapies are presented at the end.
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Affiliation(s)
- Renata Szydlak
- Chair of Medical Biochemistry, Faculty of Medicine, Jagiellonian University Medical College, Kraków 31-034, Poland
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7
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Drabik L, Mazurek A, Czyż Ł, Tekieli Ł, Szot W, Kwiecień E, Banys RP, Urbanczyk-Zawadzka M, Borkowska E, Kozynacka A, Skubera M, Brzyszczyk-Marzec M, Kostkiewicz M, Majka M, Podolec P, Musiałek P. Multi-modality imaging in the CIRCULATE-AMI pilot study cohort: a framework for an imaging-based randomized controlled trial of Wharton jelly mesenchymal stem cell use to stimulate myocardial repair/regeneration. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:496-499. [PMID: 36967846 PMCID: PMC10031681 DOI: 10.5114/aic.2023.124361] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Accepted: 03/17/2022] [Indexed: 06/18/2023] Open
Affiliation(s)
- Leszek Drabik
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | - Adam Mazurek
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | - Łukasz Czyż
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | - Łukasz Tekieli
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
- Department of Interventional Cardiology, Jagiellonian University Medical College, Krakow, Poland
| | - Wojciech Szot
- John Paul II Hospital, Krakow, Poland
- Nuclear Imaging Laboratory, Krakow, Poland
| | - Ewa Kwiecień
- Department of Cardiology and Internal Medicine, Ludwik Rydygier Memorial Specialized Hospital, Krakow, Poland
| | - Robert P. Banys
- John Paul II Hospital, Krakow, Poland
- Magnetic Resonance Imaging Laboratory, Krakow, Poland
| | | | - Eliza Borkowska
- John Paul II Hospital, Krakow, Poland
- Nuclear Imaging Laboratory, Krakow, Poland
| | - Anna Kozynacka
- John Paul II Hospital, Krakow, Poland
- Department of Coronary Artery Disease and Heart Failure, Jagiellonian University Medical College, Krakow, Poland
| | - Maciej Skubera
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | | | - Magdalena Kostkiewicz
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
- Nuclear Imaging Laboratory, Krakow, Poland
| | - Marcin Majka
- Department of Transplantation, Jagiellonian University Medical College, Krakow, Poland
| | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | - Piotr Musiałek
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
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8
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Kwiecien E, Drabik L, Mazurek A, Jarocha D, Urbanczyk M, Szot W, Banys RP, Kozynacka-Fras A, Plazak W, Olszowska M, Sobczyk D, Kostkiewicz M, Majka M, Podolec P, Musialek P. Acute myocardial infarction reparation/regeneration strategy using Wharton's jelly multipotent stem cells as an 'unlimited' therapeutic agent: 3-year outcomes in a pilot cohort of the CIRCULATE-AMI trial. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:476-482. [PMID: 36967843 PMCID: PMC10031665 DOI: 10.5114/aic.2022.121125] [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: 11/01/2021] [Accepted: 03/02/2022] [Indexed: 11/18/2022] Open
Abstract
Introduction CIRCULATE-AMI (NCT03404063), a cardiac magnetic resonance imaging (cMRI) infarct size-reduction-powered double-blind randomized controlled trial (RCT) of standardized Wharton jelly multipotent stem cells (WJMSCs, CardioCell Investigational Medical Product) vs. placebo (2 : 1) transcoronary transfer on acute myocardial infarction (AMI) day ~5-7, is preceded by safety and feasibility evaluation in a pilot study cohort (CIRCULATE-AMI PSC). Aim To evaluate WJMSC transplantation safety and evolution of left ventricular (LV) remodeling in CIRCULATE-AMI PSC. Material and methods In 10 consecutive patients (32-65 years, peak CK-MB 533 ±89 U/l, cMRI-LVEF 40.3 ±2.7%, cMRI-infarct size 20.1 ±2.8%), 30 × 106 WJMSCs were administered using a novel cell delivery-dedicated, coronary-non-occlusive method (CIRCULATE catheter). Other treatment was guideline-based. Results WJMSC transfer was safe and occurred in the absence of coronary (TIMI-3 in all) or myocardial (corrected TIMI frame count (cTFC) 45 ±8 vs. 44 ±9, p = 0.51) flow deterioration or troponin elevation. By 3 years, 1 patient died from a new, non-index territory AMI; there were no other major adverse cardiovascular and cerebrovascular events (MACCE) and no adverse events that might be related to WJMSCs. cMRI infarct size was reduced from 33.2 ±7.6 g to 25.5 ±6.4 g at 1 year and 23.1 ±5.6 g at 3 years (p = 0.03 vs. baseline). cMRI, SPECT, and echo showed a consistent, statistically significant increase in LVEF at 6-12 months (41.9 ±2.6% vs. 51.0 ±3.3%, 36.0 ±3.9% vs. 44.9 ±5.0%, and 38.4 ±2.5% vs. 48.0 ±2.1% respectively, p < 0.01 for all); the effect was sustained at 3 years. Conclusions CIRCULATE-AMI PSC data suggest that WJMSC transcoronary application ~5-7 days after large AMI in humans is feasible and safe and it may be associated with a durable LVEF improvement. CIRCULATE-AMI RCT will quantify the magnitude of LV adverse remodeling attenuation with CardioCell/placebo administration.
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Affiliation(s)
- Ewa Kwiecien
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Leszek Drabik
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Adam Mazurek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Danuta Jarocha
- Department of Transplantation, John Paul II Hospital, Krakow, Poland
- Division of Hematology, The Children’s Hospital of Philadelphia, Philadelphia, PA, USA
| | | | | | | | | | - Wojciech Plazak
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Maria Olszowska
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Dorota Sobczyk
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Magdalena Kostkiewicz
- Clinical Department, John Paul II Hospital, Krakow, Poland
- Nuclear Imaging Laboratory, Krakow, Poland
| | - Marcin Majka
- Department of Transplantation, John Paul II Hospital, Krakow, Poland
| | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
| | - Piotr Musialek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Krakow, Poland
- Clinical Department, John Paul II Hospital, Krakow, Poland
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9
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Kwiatkowski T, Zbierska-Rubinkiewicz K, Krzywon JW, Majka M, Jarocha D, Kijowski J, Brzychczy A, Musialek P, Trystula M. Combined intra-arterial and intra-muscular transfer of Wharton's jelly mesenchymal stem/stromal cells in no-option critical limb ischemia - CIRCULATE N-O CLI Pilot Study. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:439-445. [PMID: 36967850 PMCID: PMC10031676 DOI: 10.5114/aic.2022.120963] [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: 04/06/2022] [Accepted: 10/17/2022] [Indexed: 11/10/2022] Open
Abstract
Introduction Despite progress in pharmacologic and revascularization therapies, no-option critical limb ischemia poses a major clinical and societal problem. Prior cell-based strategies involved mainly autologous (limited) cell sources. Aim To evaluate the safety and feasibility of a novel ischemic tissue reparation/regeneration strategy using Wharton's jelly mesenchymal stem/stromal cells (WJMSCs) as an "unlimited" cell source in N-O CLI (first-in-man study, FIM). Material and methods Enrollment criteria included Rutherford-4 to Rutherford-6 in absence of anatomic/technical feasibility for revascularization and adequate inflow via the common femoral artery with patency of at least one below-the-knee artery. 30 × 106 WJMSCs were administered intra-arterially and intra-muscularly (50%/50%) over 3-6-week intervals (3-6 administrations). Safety, feasibility and potential signals of efficacy were assessed at 12 and 48 months. Results Five patients (age 61-71, 60% male, Rutherford-6 20%, Rutherford-5 60%, Rutherford-4 20%) were enrolled. WJMSCs were administered per protocol in absence of administration technique-related adverse events. Hyperemia, lasting 12-24 h, occurred in 4/5 subjects. Transient edema and pain (reactive to paracetamol) occurred in 3 (60%) patients. Amputation-free survival was 80% after 12 and 48 months. In those who avoided amputation, ischemic ulcerations healed and Rutherford stage improved. 4/5 patients were free of resting pain after 3-6 doses. Conclusions This FIM study demonstrated the safety and feasibility of WJMSCs use in patients with N-O CLI and suggested treatment efficacy with ≥ 3 doses. Our findings provide a basis for a randomized, double-blind clinical trial to assess the efficacy of WJMSC-based therapeutic strategy in N-O CLI patients.
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Affiliation(s)
| | | | - Jerzy W. Krzywon
- Department of Vascular Surgery, John Paul II Hospital, Krakow, Poland
| | - Marcin Majka
- Department of Transplantation, Jagiellonian University, Krakow, Poland
| | - Danuta Jarocha
- Division of Hematology, Department of Pediatrics, Children’s Hospital of Philadelphia, Philadelphia, Pennsylvania, United States
| | - Jacek Kijowski
- Department of Transplantation, Jagiellonian University, Krakow, Poland
| | - Andrzej Brzychczy
- Department of Vascular Surgery, John Paul II Hospital, Krakow, Poland
| | - Piotr Musialek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Krakow, Poland
| | - Mariusz Trystula
- Department of Vascular Surgery, John Paul II Hospital, Krakow, Poland
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Czyż Ł, Tekieli Ł, Miszalski-Jamka T, Banyś RP, Szot W, Mazur W, Chmiel J, Mazurek A, Skubera M, Dąbrowski W, Jarocha D, Podolec P, Majka M, Musiałek P. Infarct size and long-term left ventricular remodelling in acute myocardial infarction patients subjected to transcoronary delivery of progenitor cells. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:465-471. [PMID: 36967855 PMCID: PMC10031670 DOI: 10.5114/aic.2023.125079] [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: 01/17/2022] [Accepted: 06/21/2022] [Indexed: 02/18/2023] Open
Abstract
Introduction Infarct size (IS) is a fundamental determinant of left-ventricular (LV) remodelling (end-systolic and end-diastolic volume change, ΔESV, ΔEDV) and adverse clinical outcomes after myocardial infarction (MI). Our prior work found that myocardial uptake of transcoronary-delivered progenitor cells is governed by IS. Aim To evaluate the relationship between IS, stem cell uptake, and the magnitude of LV remodelling in patients receiving transcoronary administration of progenitor cells shortly after MI. Material and methods Thirty-one subjects (age 36-69 years) with primary percutaneous coronary intervention (pPCI)-treated anterior ST-elevation MI (peak CK-MB 584 [181-962] U/l, median [range]) and sustained left ventricle ejection fraction (LVEF) ≤ 45% were studied. On day 10 (median) 4.3 × 106 (median) autologous CD34+ cells (50% labelled with 99mTc-extametazime) were administered via the infarct-related artery (left anterior descending). ΔESV, ΔEDV, and mid circumferential myocardial strain (mCS) were evaluated at 24 months. Results Infarct mass (cMRI) was 57 [11-112] g. Cell label myocardial uptake (whole-body γ-scans) was proportional to IS (r = 0.62), with a median 2.9% uptake in IS 1st tercile (≤ 45 g), 5.2% in 2nd (46-76 g), and 6.7% in 3rd (> 76 g) (p = 0.0006). Cell uptake in proportion to IS attenuated the IS-ΔESV (p = 0.41) and IS-ΔEDV (p = 0.09) relationship. At 24 months, mCS improved in IS 2nd tercile (p = 0.028) while it showed no significant change in smaller (p = 0.87) or larger infarcts (p = 0.58). Conclusions This largest human study with labelled CD34+ cell transplantation shortly after MI suggests that cell uptake (proportional to IS) may attenuate the effect of IS on LV adverse remodelling. To boost this effect, further strategies should involve cell types and delivery techniques to maximize myocardial uptake.
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Affiliation(s)
- Łukasz Czyż
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Łukasz Tekieli
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
- Department of Interventional Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | | | - R. Paweł Banyś
- Department of Radiology, John Paul II Hospital, Krakow, Poland
| | - Wojciech Szot
- Nuclear Imaging Laboratory, John Paul II Hospital, Krakow, Poland
| | - Wojciech Mazur
- Division of Cardiology, The Christ Hospital Health Network, Cincinnati, United States of America
| | - Jakub Chmiel
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Adam Mazurek
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Maciej Skubera
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Władysław Dąbrowski
- Department of Interventional Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Danuta Jarocha
- Division of Hematology, Children’s Hospital of Philadelphia, Philadelphia, United States of America
| | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Institute of Pediatrics, Jagiellonian University Medical College, Krakow, Poland
| | - Piotr Musiałek
- Department of Cardiac and Vascular Diseases, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
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Dabrowski W, Tekieli L, Mazurek A, Lanocha M, Banys RP, Zmudka K, Majka M, Wojakowski W, Tendera M, Musialek P. Transcoronary stem cell transfer and evolution of infarct-related artery atherosclerosis: evaluation with conventional and novel imaging techniques including Quantitative Virtual Histology (qVH). ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:483-495. [PMID: 36967840 PMCID: PMC10031661 DOI: 10.5114/aic.2023.125609] [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: 05/06/2022] [Accepted: 10/21/2022] [Indexed: 03/12/2023] Open
Abstract
Introduction It has been suggested that infarct-related artery (IRA) atherosclerosis progression after stem cell transcoronary administration might represent a stem-cell mediated adverse effect. Aim To evaluate, using conventional (quantitative coronary angiography, QCA, intravascular ultrasound - IVUS) and novel (quantitative virtual histology - qVH) tools, evolution of IRA atherosclerosis following transcoronary stem cell transfer. Material and methods QCA, IVUS, VH-IVUS and qVH were performed in 22 consecutive patients (4 women) aged 59 years (data provided as median) undergoing a distal-to-stent infusion of 2.21 × 106 CD34+CXCR4+ autologous bone marrow cells via a cell delivery-dedicated perfusion catheter at anterior AMI day 7. Imaging was repeated at 12 months. This was a substudy of Myocardial Regeneration by Intracoronary Infusion of Selected Population of Stem Cells in Acute Myocardial Infarction (REGENT) Trial (NCT00316381). Results 18.2% subjects showed absence of distal-to-stent angiographic/IVUS atherosclerotic lesion(s) at baseline and no new lesion(s) at 12-months. In the remaining cohort, there were 28 lesions by QCA (32 by IVUS) at baseline and no new lesion(s) at follow-up. Three fibroatheromas evolved (2 to calcified fibroatheroma and 1 to a fibrocalcific lesion); other plaques maintained their stable (low-risk) phenotypes. Diameter stenosis of QCA-identified lesions was 29.5 vs. 26.5% (p = 0.012, baseline vs. 12-months). Gray-scale IVUS showed reduction in area stenosis (33.8 vs. 31.0%, p = 0.004) and plaque burden (66.27 vs. 64.56%, p = 0.009) at 12-months. Peak fibrotic plaque content increased from 70.41% to 75.0% (p = 0.004). qVH peak confluent necrotic core area and minimal fibrous cap thickness remained stable (0.64 vs. 0.59 mm2, p = 0.290, and 0.15 vs. 0.16 mm, p = 0.646). Conclusions This study, using a range of classic and novel imaging techniques, indicates lack of any stimulatory effect of transcoronary stem cell transfer on coronary atherosclerosis. Whether, and to what extent, a moderate reduction in plaque burden and stenosis severity at 12-months results from optimized pharmacotherapy and/or stem cell transfer requires further elucidation.
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Affiliation(s)
- Wladyslaw Dabrowski
- Department of Interventional Cardiology, Jagiellonian University Institute of Cardiology, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | - Lukasz Tekieli
- Department of Interventional Cardiology, Jagiellonian University Institute of Cardiology, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Institute of Cardiology, John Paul II Hospital, Krakow, Poland
| | - Adam Mazurek
- John Paul II Hospital, Krakow, Poland
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Institute of Cardiology, John Paul II Hospital, Krakow, Poland
| | | | - R. Pawel Banys
- Department of Radiology, John Paul II Hospital, Krakow, Poland
| | - Krzysztof Zmudka
- Department of Interventional Cardiology, Jagiellonian University Institute of Cardiology, Krakow, Poland
- John Paul II Hospital, Krakow, Poland
| | - Marcin Majka
- Jagiellonian University Department of Transplantation, Krakow, Poland
| | - Wojciech Wojakowski
- Division of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland
| | - Michal Tendera
- Division of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland
| | - Piotr Musialek
- John Paul II Hospital, Krakow, Poland
- Department of Cardiac and Vascular Diseases, Jagiellonian University, Institute of Cardiology, John Paul II Hospital, Krakow, Poland
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12
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Kwiatkowski T, Zbierska-Rubinkiewicz K, Krzywoń JW, Szkółka Ł, Kuczmik W, Majka M, Maga P, Drelicharz Ł, Musiałek P, Trystuła M. Cellular therapies in no-option critical limb ischemia: present status and future directions. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2022; 18:340-349. [PMID: 36967860 PMCID: PMC10031679 DOI: 10.5114/aic.2022.120962] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2022] [Accepted: 10/10/2022] [Indexed: 11/10/2022] Open
Abstract
Critical limb ischemia - an advanced stage of lower extremity arterial disease with presence of rest pain and/or ischemic ulcers - remains an important cause of major amputations and disability in developed societies. Novel treatment strategies are urgently needed to prevent (or delay) amputations in particular for patients in whom effective revascularization is no longer feasible for anatomic and/or technical reasons (no-option critical limb ischemia - N-O CLI). Cellular therapies have been gaining the growing attention of researchers and clinicians in the last two decades. Several cell types have been used in pre-clinical and clinical studies, and a number of mechanisms have been proposed to contribute to vascular reparation and regeneration in N-O CLI. Although early trials suggested clinical improvement with use of cell-based therapies in N-O CLI, meta-analyses that included randomized controlled trials have not provided definitive conclusions. Fundamental limitations have involved poorly defined cell lines/populations, limited numbers of study participants and limited follow-up periods, and enrolling patients "too sick to benefit" (such as those in Rutherford class 6). Recent advances include standardized "unlimited" sources of therapeutic cells and better understanding of mechanisms that may contribute to vascular reparation and regeneration. Furthermore, based on recent pre-clinical and clinical studies, cell-free preparations (such as microvesicle-based) are being increasingly developed along with advanced therapy medical products consisting of engineered cells and pro-angiogenic factors.
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Affiliation(s)
- Tomasz Kwiatkowski
- Department of Vascular Surgery and Endovascular Interventions, John Paul II Hospital, Krakow, Poland
| | | | - Jerzy W. Krzywoń
- Depratment of Vascular Surgery, University Hospital, Krakow, Poland
| | - Łukasz Szkółka
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland
| | - Wacław Kuczmik
- Department of General Surgery, Vascular Surgery, Angiology and Phlebology, Medical University of Silesia, Katowice, Poland
| | - Marcin Majka
- Department of Transplantation, Jagiellonian University Medical College, Krakow, Poland
| | - Paweł Maga
- Department of Angiology, University Hospital, Krakow, Poland
| | | | - Piotr Musiałek
- Department of Cardiac and Vascular Diseases, Institute of Cardiology, Jagiellonian University Medical College, John Paul II Hospital, Krakow, Poland
| | - Mariusz Trystuła
- Department of Vascular Surgery and Endovascular Interventions, John Paul II Hospital, Krakow, Poland
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Liu J, Liang X, Li M, Lin F, Ma X, Xin Y, Meng Q, Zhuang R, Zhang Q, Han W, Gao L, He Z, Zhou X, Liu Z. Intramyocardial injected human umbilical cord-derived mesenchymal stem cells (HucMSCs) contribute to the recovery of cardiac function and the migration of CD4 + T cells into the infarcted heart via CCL5/CCR5 signaling. Stem Cell Res Ther 2022; 13:247. [PMID: 35690805 PMCID: PMC9188247 DOI: 10.1186/s13287-022-02914-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 05/25/2022] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Human umbilical cord-derived mesenchymal stem cells (HucMSCs) have been recognized as a promising cell for treating myocardial infarction (MI). Inflammatory response post MI is critical in determining the cardiac function and subsequent adverse left ventricular remodeling. However, the local inflammatory effect of HucMSCs after intramyocardial injection in murine remains unclear. METHODS HucMSCs were cultured and transplanted into the mice after MI surgery. Cardiac function of mice were analyzed among MI-N.S, MI-HucMSC and MI-HucMSC-C-C Motif Chemokine receptor 5 (CCR5) antagonist groups, and angiogenesis, fibrosis and hypertrophy, and immune cells infiltration of murine hearts were evaluated between MI-N.S and MI-HucMSC groups. We detected the expression of inflammatory cytokines and their effects on CD4+ T cells migration. RESULTS HucMSCs treatment can significantly improve the cardiac function and some cells can survive at least 28 days after MI. Intramyocardial administration of HucMSCs also improved angiogenesis and alleviated cardiac fibrosis and hypertrophy. Moreover, we found the much higher numbers of CD4+ T cells and CD4+FoxP3+ regulatory T cells (Tregs) in the heart with HucMSCs than that with N.S treatment on day 7 post MI. In addition, the protein level of C-C Motif Chemokine Ligand 5 (CCL5) greatly increased in HucMSCs treated heart compared to MI-N.S group. In vitro, HucMSCs inhibited CD4+ T cells migration and addition of CCL5 antibody or CCR5 antagonist significantly reversed this effect. In vivo results further showed that addition of CCR5 antagonist can reduce the cardioprotective effect of HucMSCs administration on day 7 post MI injury. CONCLUSION These findings indicated that HucMSCs contributed to cardiac functional recovery and attenuated cardiac remodeling post MI. Intramyocardial injection of HucMSCs upregulated the CD4+FoxP3+ Tregs and contributed to the migration of CD4+ T cells into the injured heart via CCL5/CCR5 pathway.
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Affiliation(s)
- Jing Liu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Burn and Plastic Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, Beijing, 100045, People's Republic of China
| | - Xiaoting Liang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, People's Republic of China
| | - Mimi Li
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Fang Lin
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Xiaoxue Ma
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Yuanfeng Xin
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
| | - Qingshu Meng
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
| | - Rulin Zhuang
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China
| | - Qingliu Zhang
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
| | - Wei Han
- Department of Heart Failure, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
| | - Ling Gao
- Translational Medical Center for Stem Cell Therapy and Institute for Regenerative Medicine, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200123, People's Republic of China
| | - Zhiying He
- Institute for Regenerative Medicine, Shanghai East Hospital, School of Life Sciences and Technology, Tongji University, Shanghai, 200120, People's Republic of China
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China
- Shanghai Engineering Research Center of Stem Cells Translational Medicine, Shanghai, 200335, People's Republic of China
| | - Xiaohui Zhou
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
| | - Zhongmin Liu
- Research Center for Translational Medicine, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Heart Failure Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, People's Republic of China.
- Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, 150 Jimo Rd, Pudong, Shanghai, 200120, People's Republic of China.
- Shanghai Institute of Stem Cell Research and Clinical Translation, Shanghai, 200120, People's Republic of China.
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Gokce C, Gurcan C, Delogu LG, Yilmazer A. 2D Materials for Cardiac Tissue Repair and Regeneration. Front Cardiovasc Med 2022; 9:802551. [PMID: 35224044 PMCID: PMC8873146 DOI: 10.3389/fcvm.2022.802551] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/13/2022] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs) have a massive impact on human health. Due to the limited regeneration capacity of adult heart tissue, CVDs are the leading cause of death and disability worldwide. Even though there are surgical and pharmacological treatments for CVDs, regenerative strategies are the most promising approaches and have the potential to benefit millions of people. As in any other tissue engineering approach, the repair and regeneration of damaged cardiac tissues generally involve scaffolds made up of biodegradable and biocompatible materials, cellular components such as stem cells, and growth factors. This review provides an overview of biomaterial-based tissue engineering approaches for CVDs with a specific focus on the potential of 2D materials. It is essential to consider both physicochemical and immunomodulatory properties for evaluating the applicability of 2D materials in cardiac tissue repair and regeneration. As new members of the 2D materials will be explored, they will quickly become part of cardiac tissue engineering technologies.
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Affiliation(s)
- Cemile Gokce
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
| | - Cansu Gurcan
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
| | | | - Acelya Yilmazer
- Department of Biomedical Engineering, Ankara University, Ankara, Turkey
- Stem Cell Institute, Ankara University, Ankara, Turkey
- *Correspondence: Acelya Yilmazer
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15
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Abstract
Mesenchymal stem cells (MSCs) exhibit regenerative and reparative properties. However, most MSC-related studies remain to be translated for regular clinical usage, partly due to challenges in pre-transplantation cell labelling and post-transplantation cell tracking. Amidst this, there are growing concerns over the toxicity of commonly used gadolinium-based contrast agents that mediate in-vivo cell detection via MRI. This urges to search for equally effective but less toxic alternatives that would facilitate and enhance MSC detection post-administration and provide therapeutic benefits in-vivo. MSCs labelled with iron oxide nanoparticles (IONPs) have shown promising results in-vitro and in-vivo. Thus, it would be useful to revisit these studies before inventing new labelling approaches. Aiming to inform regenerative medicine and augment clinical applications of IONP-labelled MSCs, this review collates and critically evaluates the utility of IONPs in enhancing MSC detection and therapeutics. It explains the rationale, principle, and advantages of labelling MSCs with IONPs, and describes IONP-induced intracellular alterations and consequent cellular manifestations. By exemplifying clinical pathologies, it examines contextual in-vitro, animal, and clinical studies that used IONP-labelled bone marrow-, umbilical cord-, adipose tissue- and dental pulp-derived MSCs. It compiles and discusses studies involving MSC-labelling of IONPs in combinations with carbohydrates (Venofer, ferumoxytol, dextran, glucosamine), non-carbohydrate polymers [poly(L-lysine), poly(lactide-co-glycolide), poly(L-lactide), polydopamine], elements (ruthenium, selenium, gold, zinc), compounds/stains (silica, polyethylene glycol, fluorophore, rhodamine B, DAPI, Prussian blue), DNA, Fibroblast growth Factor-2 and the drug doxorubicin. Furthermore, IONP-labelling of MSC exosomes is reviewed. Also, limitations of IONP-labelling are addressed and methods of tackling those challenges are suggested.
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16
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Krzyżak AT, Habina‐Skrzyniarz I, Mazur W, Sułkowski M, Kot M, Majka M. Nuclear magnetic resonance footprint of Wharton Jelly mesenchymal stem cells death mechanisms and distinctive in‐cell biophysical properties in vitro. J Cell Mol Med 2022; 26:1501-1514. [PMID: 35076984 PMCID: PMC8899161 DOI: 10.1111/jcmm.17178] [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: 08/27/2021] [Revised: 11/04/2021] [Accepted: 12/22/2021] [Indexed: 01/29/2023] Open
Abstract
The importance of the biophysical characterization of mesenchymal stem cells (MSCs) was recently pointed out for supporting the development of MSC‐based therapies. Among others, tracking MSCs in vivo and a quantitative characterization of their regenerative impact by nuclear magnetic resonance (NMR) demands a full description of MSCs’ MR properties. In the work, Wharton Jelly MSCs are characterized in a low magnetic field (LF) in vitro by using different approaches. They encompass various settings: MSCs cultured in a Petri dish and cell suspensions; experiments‐ 1D‐T1, 1D‐T2, 1D diffusion, 2D T1‐T2 and D‐T2; devices‐ with a bore aperture and single‐sided one. Complex NMR analysis with the aid of random walk simulations allows the determination of MSCs T1 and T2 relaxation times, cells and nuclei sizes, self‐diffusion coefficients of the nucleus and cytoplasm. In addition, the influence of a single layer of cells on the effective diffusion coefficient of water is detected with the application of a single‐sided NMR device. It also enables the identification of apoptotic and necrotic cell death and changed diffusional properties of cells suspension caused by compressing forces induced by the subsequent cell layers. The study delivers MSCs‐specific MR parameters that may help tracking MSCs in vivo.
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Affiliation(s)
- Artur T. Krzyżak
- Faculty of Geology, Geophysics and Environmental Protection AGH University of Science and Technology Cracow Poland
| | - Iwona Habina‐Skrzyniarz
- Faculty of Geology, Geophysics and Environmental Protection AGH University of Science and Technology Cracow Poland
| | - Weronika Mazur
- Faculty of Geology, Geophysics and Environmental Protection AGH University of Science and Technology Cracow Poland
- Faculty of Physics and Applied Computer Science AGH University of Science and Technology Cracow Poland
| | - Maciej Sułkowski
- Department of Transplantation, Faculty of Medicine, Institute of Pediatrics Jagiellonian University Medical College Cracow Poland
| | - Marta Kot
- Department of Transplantation, Faculty of Medicine, Institute of Pediatrics Jagiellonian University Medical College Cracow Poland
| | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Institute of Pediatrics Jagiellonian University Medical College Cracow Poland
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Nernpermpisooth N, Sarre C, Barrere C, Contreras R, Luz-Crawford P, Tejedor G, Vincent A, Piot C, Kumphune S, Nargeot J, Jorgensen C, Barrère-Lemaire S, Djouad F. PPARβ/δ Is Required for Mesenchymal Stem Cell Cardioprotective Effects Independently of Their Anti-inflammatory Properties in Myocardial Ischemia-Reperfusion Injury. Front Cardiovasc Med 2021; 8:681002. [PMID: 34616778 PMCID: PMC8488150 DOI: 10.3389/fcvm.2021.681002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Accepted: 08/24/2021] [Indexed: 11/17/2022] Open
Abstract
Myocardial infarction ranks first for the mortality worldwide. Because the adult heart is unable to regenerate, fibrosis develops to compensate for the loss of contractile tissue after infarction, leading to cardiac remodeling and heart failure. Adult mesenchymal stem cells (MSC) regenerative properties, as well as their safety and efficacy, have been demonstrated in preclinical models. However, in clinical trials, their beneficial effects are controversial. In an experimental model of arthritis, we have previously shown that PPARβ/δ deficiency enhanced the therapeutic effect of MSC. The aim of the present study was to compare the therapeutic effects of wild-type MSC (MSC) and MSC deficient for PPARβ/δ (KO MSC) perfused in an ex vivo mouse model of ischemia-reperfusion (IR) injury. For this purpose, hearts from C57BL/6J mice were subjected ex vivo to 30 min ischemia followed by 1-h reperfusion. MSC and KO MSC were injected into the Langendorff system during reperfusion. After 1 h of reperfusion, the TTC method was used to assess infarct size. Coronary effluents collected in basal condition (before ischemia) and after ischemia at 1 h of reperfusion were analyzed for their cytokine profiles. The dose-response curve for the cardioprotection was established ex vivo using different doses of MSC (3.105, 6.105, and 24.105 cells/heart) and the dose of 6.105 MSC was found to be the optimal concentration. We showed that the cardioprotective effect of MSC was PPARβ/δ-dependent since it was lost using KO MSC. Moreover, cytokine profiling of the coronary effluents collected in the eluates after 60 min of reperfusion revealed that MSC treatment decreases CXCL1 chemokine and interleukin-6 release compared with untreated hearts. This anti-inflammatory effect of MSC was also observed when hearts were treated with PPARβ/δ-deficient MSC. In conclusion, our study revealed that the acute cardioprotective properties of MSC in an ex vivo model of IR injury, assessed by a decreased infarct size at 1 h of reperfusion, are PPARβ/δ-dependent but not related to their anti-inflammatory effects.
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Affiliation(s)
- Nitirut Nernpermpisooth
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Integrative Biomedical Research Unit, Naresuan University, Phitsanulok, Thailand
| | - Charlotte Sarre
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France
| | - Christian Barrere
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Rafaël Contreras
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France
| | - Patricia Luz-Crawford
- Institute for Regenerative Medicine and Biotherapy, Université de Montpellier, INSERM, Montpellier, France.,Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
| | - Gautier Tejedor
- MedXCell Science, Institute for Regenerative Medicine and Biotherapy, Montpellier, France
| | - Anne Vincent
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Christophe Piot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France.,Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Sarawut Kumphune
- Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Integrative Biomedical Research Unit, Naresuan University, Phitsanulok, Thailand.,Biomedical Engineering Institute, Chiang Mai University, Chiang Mai, Thailand
| | - Joel Nargeot
- Institut de Génomique Fonctionnelle, Université de Montpellier, CNRS, INSERM, Montpellier, France
| | - Christian Jorgensen
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,Centre Hospitalier Universitaire Montpellier, Montpellier, France
| | | | - Farida Djouad
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile
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18
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Khazaei S, Soleimani M, Tafti SHA, Aghdam RM, Hojati Z. Improvement of Heart Function After Transplantation of Encapsulated Stem Cells Induced with miR-1/Myocd in Myocardial Infarction Model of Rat. Cell Transplant 2021; 30:9636897211048786. [PMID: 34606735 PMCID: PMC8493326 DOI: 10.1177/09636897211048786] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
Cardiovascular disease is one of the most common causes of death worldwide. Mesenchymal stem cells (MSCs) are one of the most common sources in cell-based therapies in heart regeneration. There are several methods to differentiate MSCs into cardiac-like cells, such as gene induction. Moreover, using a three-dimensional (3D) culture, such as hydrogels increases efficiency of differentiation. In the current study, mouse adipose-derived MSCs were co-transduced with lentiviruses containing microRNA-1 (miR-1) and Myocardin (Myocd). Then, expression of cardiac markers, such as NK2 homeobox 5(Nkx2-5), GATA binding protein 4 (Gata4), and troponin T type 2 (Tnnt2) was investigated, at both gene and protein levels in two-dimensional (2D) culture and chitosan/collagen hydrogel (CS/CO) as a 3D culture. Additionally, after induction of myocardial infarction (MI) in rats, a patch containing the encapsulated induced cardiomyocytes (iCM/P) was implanted to MI zone. Subsequently, 30 days after MI induction, echocardiography, immunohistochemistry staining, and histological examination were performed to evaluate cardiac function. The results of quantitative real -time polymerase chain reaction (qRT-PCR) and immunocytochemistry showed that co-induction of miR-1 and Myocd in MSCs followed by 3D culture of transduced cells increased expression of cardiac markers. Besides, results of in vivo study implicated that heart function was improved in MI model of rats in iCM/P-treated group. The results suggested that miR-1/Myocd induction combined with encapsulation of transduced cells in CS/CO hydrogel increased efficiency of MSCs differentiation into iCMs and could improve heart function in MI model of rats after implantation.
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Affiliation(s)
- Samaneh Khazaei
- Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, Isfahan University, Isfahan, Iran
| | - Masoud Soleimani
- Tissue Engineering and Hematology Department, Faculty of Medical Sciences, Tarbiat Modares University, Tehran, Iran.,Tissue Engineering and Nanomedicine Research Center, School of Advanced Technologies in Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Seyed Hossein Ahmadi Tafti
- Research Center for Advanced Technologies in Cardiovascular Medicine, Tehran heart Center, Tehran University of Medical Sciences, Tehran, Iran
| | | | - Zohreh Hojati
- Department of Cell and Molecular Biology, Faculty of Biological Science and Technology, Isfahan University, Isfahan, Iran
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Ali A, Shibu MA, Kuo CH, Lo JF, Chen RJ, Day CH, Ho TJ, PadmaViswanadha V, Kuo WW, Huang CY. CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells attenuate hyperglycemia-induced oxidative stress-mediated kidney injuries in diabetic rats. Free Radic Biol Med 2021; 173:70-80. [PMID: 34298092 DOI: 10.1016/j.freeradbiomed.2021.07.026] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Revised: 07/08/2021] [Accepted: 07/20/2021] [Indexed: 12/27/2022]
Abstract
Accumulating studies have demonstrated the protective roles of mesenchymal stem cells against several disorders. However, one of their crucial limitations is reduced viability under stress conditions, including the hyperglycemia induced by diabetes. The molecular mechanisms involved in diabetes-induced kidney injuries are not fully elucidated. In this study, we found that high glucose (HG) reduced human proximal tubular epithelial cell viability. Further, hyperglycemia induced oxidative stress-mediated apoptosis and fibrosis in HK-2 cells via activation of the mitogen-activated protein kinases (MAPKs) including c-Jun N-terminal kinase JNK and p38 kinase. Carboxyl terminus of HSP70 interacting protein (CHIP) overactivation considerably rescued cell viability under HG stress. Moreover, Western blot analysis, flow cytometry, and MitoSOX staining revealed that hyperglycemia-induced mitochondrial oxidative stress production and apoptosis were attenuated in CHIP-overexpressing Wharton's jelly-derived mesenchymal stem cells (WJMSCs). Co-culture with CHIP-expressing WJMSCs maintained HK-2 cell viability, and inhibited apoptosis and fibrosis by attenuating HG-induced ROS-mediated MAPK activation. CHIP-overexpressing WJMSCs also rescued the decreased kidney weight and hyperglycemia-induced kidney damage observed in streptozotocin-induced diabetic rats. Cumulatively, the current research findings demonstrate that CHIP suppresses hyperglycemia-induced oxidative stress and confers resistance to MAPK-induced apoptosis and fibrosis, and suggests that CHIP protects WJMSCs and the high quality WJMSCs have therapeutic effects against diabetes-induced kidney injuries.
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Affiliation(s)
- Ayaz Ali
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan
| | - Marthandam Asokan Shibu
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Since Medical Foundation, Hualien, 970, Taiwan
| | - Chia-Hua Kuo
- Laboratory of Exercise Biochemistry, University of Taipei, Taipei, Taiwan
| | - Jeng-Feng Lo
- Institute of Oral Biology, National Yang-Ming University, Taipei, Taiwan
| | - Ray-Jade Chen
- Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei, 110, Taiwan
| | | | - Tsung-Jung Ho
- Department of Chinese Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Tzu Chi University, Hualien, Taiwan; Integration Center of Traditional Chinese and Modern Medicine, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien, Taiwan
| | | | - Wei-Wen Kuo
- Department of Biological Science and Technology, China Medical University, Taichung, 404, Taiwan; Ph.D. Program for Biotechnology Industry, China Medical University, Taichung, 406, Taiwan
| | - Chih-Yang Huang
- Cardiovascular and Mitochondrial Related Disease Research Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Since Medical Foundation, Hualien, 970, Taiwan; Graduate Institute of Biomedical Sciences, China Medical University, Taichung, 404, Taiwan; Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan; Department of Biotechnology, Asia University, Taichung, Taiwan; Center of General Education, Buddhist Tzu Chi Medical Foundation, Tzu Chi University of Science and Technology, Hualien, 970, Taiwan.
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20
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Mazur W, Urbańczyk-Zawadzka M, Banyś R, Obuchowicz R, Trystuła M, Krzyżak AT. Diffusion as a Natural Contrast in MR Imaging of Peripheral Artery Disease (PAD) Tissue Changes. A Case Study of the Clinical Application of DTI for a Patient with Chronic Calf Muscles Ischemia. Diagnostics (Basel) 2021; 11:diagnostics11010092. [PMID: 33429993 PMCID: PMC7827719 DOI: 10.3390/diagnostics11010092] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Accepted: 01/05/2021] [Indexed: 02/06/2023] Open
Abstract
This paper reports a first application of diffusion tensor imaging with corrections by using the B-matrix spatial distribution method (BSD-DTI) for peripheral artery disease (PAD) detected in the changes of diffusion tensor parameters (DTPs). A 76-year-old male was diagnosed as having PAD, since he demonstrated in angiographic images of lower legs severe arterial stenosis and the presence of lateral and peripheral circulation and assigned to the double-blind RCT using mesenchymal stem cells (MSCs) or placebo for the regenerative treatment of implications of ischemic diseases. In order to indicate changes in diffusivity in calf muscles in comparison to a healthy control, a DTI methodology was developed. The main advantage of the applied protocol was decreased scanning time, which was achieved by reducing b-value and number of scans (to 1), while maintaining minimal number of diffusion gradient directions and high resolution. This was possible due to calibration via the BSD method, which reduced systematic errors and allowed quantitative analysis. In the course of PAD, diffusivities were elevated across the calf muscles in posterior compartment and lost their anisotropy. Different character was noticed for anterior compartment, in which diffusivities along and across muscles were decreased without a significant loss of anisotropy. After the intervention involving a series of injections, the improvement of DTPs and tractography was visible, but can be assigned neither to MSCs nor placebo before unblinding.
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Affiliation(s)
- Weronika Mazur
- Faculty of Geology, Geophysics and Environmental Protection, AGH University of Science and Technology, Mickiewicza Avenue 30, 30-059 Cracow, Poland;
- Faculty of Physics and Applied Computer Science, AGH University of Science and Technology, Mickiewicza Avenue 30, 30-059 Cracow, Poland
| | - Małgorzata Urbańczyk-Zawadzka
- Department of Radiology and Diagnostic Imaging, John Paul II Hospital, Prądnicka Street 80, 31-202 Cracow, Poland; (M.U.-Z.); (R.B.)
| | - Robert Banyś
- Department of Radiology and Diagnostic Imaging, John Paul II Hospital, Prądnicka Street 80, 31-202 Cracow, Poland; (M.U.-Z.); (R.B.)
| | - Rafał Obuchowicz
- Department of Diagnostic Imaging, Jagiellonian University Medical College, Jakubowskiego 2, 30-688 Cracow, Poland;
| | - Mariusz Trystuła
- Department of Vascular Surgery with Endovascular Procedures Subdivision, John Paul II Hospital, Prądnicka Street 80, 31-202 Cracow, Poland;
| | - Artur T. Krzyżak
- Faculty of Geology, Geophysics and Environmental Protection, AGH University of Science and Technology, Mickiewicza Avenue 30, 30-059 Cracow, Poland;
- Correspondence:
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21
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Ulus AT, Mungan C, Kurtoglu M, Celikkan FT, Akyol M, Sucu M, Toru M, Gul SS, Cinar O, Can A. Intramyocardial Transplantation of Umbilical Cord Mesenchymal Stromal Cells in Chronic Ischemic Cardiomyopathy: A Controlled, Randomized Clinical Trial (HUC-HEART Trial). Int J Stem Cells 2020; 13:364-376. [PMID: 32840230 PMCID: PMC7691850 DOI: 10.15283/ijsc20075] [Citation(s) in RCA: 28] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 06/18/2020] [Accepted: 07/06/2020] [Indexed: 01/15/2023] Open
Abstract
Background and Objectives The HUC-HEART Trial (ClinicalTrials.gov Identifier: NCT02323477) was a controlled, prospective, phase I/II, multicenter, single-blind, three-arm randomized study of intramyocardial delivery of human umbilical cord-derived mesenchymal stromal cells (HUC-MSCs) combined with coronary artery bypass-grafting (CABG) in patients with chronic ischemic cardiomyopathy (CIC). The trial aimed to assess (i) the safety and the efficacy of cell transplantation during one-year follow-up, (ii) to compare the efficacy of HUC-MSCs with autologous bone-marrow- derived mononuclear cells (BM-MNCs) in the same clinical settings. Methods and Results Fifty-four patients who were randomized to receive HUC-MSCs (23×106) (n=26) or BM-MNCs (70×107) (n=12) in combination with CABG surgery. The control patients (n=16) received no cells/vehicles but CABG intervention. All patients were screened at baseline and 1, 3, 6, 12 months after transplantation. Forty-six (85%) patients completed 12 months follow-up. No short/mid-term adverse events were encountered. Decline in NT-proBNP (baseline∼ 6 months) in both cell-treated groups; an increase in left ventricular ejection fraction (LVEF) (5.4%) and stroke volume (19.7%) were noted (baseline∼6 or 12 months) only in the HUC-MSC group. Decreases were also detected in necrotic myocardium as 2.3% in the control, 4.5% in BM-MNC, and 7.7% in the HUC-MSC groups. The 6-min walking test revealed an increase in the control (14.4%) and HUC-MSC (23.1%) groups. Conclusions Significant findings directly related to the intramyocardial delivery of HUC-MSCs justified their efficacy in CIC. Stricter patient selection criteria with precisely aligned cell dose and delivery intervals, rigorous follow-up by detailed diagnostic approaches would further help to clarify the responsiveness to the therapy.
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Affiliation(s)
- A Tulga Ulus
- Department of Cardiovascular Surgery, Hacettepe University Faculty of Medicine, Ankara, Turkey
| | - Ceren Mungan
- Ankara University Biotechnology Institute and Sisbiyotek, Ankara, Turkey
| | - Murat Kurtoglu
- Cardiovascular Surgery Division, Ankara Guven Hospital, Ankara, Turkey
| | - Ferda Topal Celikkan
- Department of Histology and Embryology, Laboratory for Stem Cells and Reproductive Cell Biology, Ankara University School of Medicine, Ankara, Turkey
| | - Mesut Akyol
- Department of Biostatistics, Ankara Yildirim Beyazit University, Ankara, Turkey
| | - Merve Sucu
- Ankara University Biotechnology Institute and Sisbiyotek, Ankara, Turkey
| | - Mustafa Toru
- Radiology Division, Ankara Liv Hospital, Ankara, Turkey
| | | | - Ozgur Cinar
- Department of Histology and Embryology, Laboratory for Stem Cells and Reproductive Cell Biology, Ankara University School of Medicine, Ankara, Turkey
| | - Alp Can
- Department of Histology and Embryology, Laboratory for Stem Cells and Reproductive Cell Biology, Ankara University School of Medicine, Ankara, Turkey
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22
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Jadczyk T, Caluori G, Wojakowski W, Starek Z. Nanotechnology and stem cells in vascular biology. VASCULAR BIOLOGY 2020; 1:H103-H109. [PMID: 32923961 PMCID: PMC7439937 DOI: 10.1530/vb-19-0021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/19/2019] [Accepted: 09/24/2019] [Indexed: 12/03/2022]
Abstract
Nanotechnology and stem cells are one of the most promising strategies for clinical medicine applications. The article provides an up-to-date view on advances in the field of regenerative and targeted vascular therapies describing a molecular design (propulsion mechanism, composition, target identification) and applications of nanorobots. Stem cell paragraph presents current clinical application of various cell types involved in vascular biology including mesenchymal stem cells, very small embryonic-like stem cells, induced pluripotent stem cells, mononuclear stem cells, amniotic fluid-derived stem cells and endothelial progenitor cells. A possible bridging between the two fields is also envisioned, where bio-inspired, safe, long-lasting nanorobots can fully target the cellular specific cues and even drive vascular process in a timely manner.
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Affiliation(s)
- Tomasz Jadczyk
- Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland.,Interventional Cardiac Electrophysiology Group, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic
| | - Guido Caluori
- Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland.,Nanobiotechnology, CEITEC-MU, Brno, Czech Republic
| | - Wojciech Wojakowski
- Department of Cardiology and Structural Heart Diseases, Medical University of Silesia, Katowice, Poland
| | - Zdenek Starek
- Interventional Cardiac Electrophysiology Group, International Clinical Research Center, St. Anne's University Hospital Brno, Brno, Czech Republic.,First Department of Internal Medicine, Cardioangiology, St. Anne's University Hospital Brno, Masaryk University, Brno, Czech Republic
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23
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Abbaszadeh H, Ghorbani F, Derakhshani M, Movassaghpour AA, Yousefi M, Talebi M, Shamsasenjan K. Regenerative potential of Wharton's jelly-derived mesenchymal stem cells: A new horizon of stem cell therapy. J Cell Physiol 2020; 235:9230-9240. [PMID: 32557631 DOI: 10.1002/jcp.29810] [Citation(s) in RCA: 57] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2020] [Accepted: 04/17/2020] [Indexed: 12/14/2022]
Abstract
Umbilical cord Wharton's jelly-derived mesenchymal stem cells (WJ-MSCs) have recently gained considerable attention in the field of regenerative medicine. Their high proliferation rate, differentiation ability into various cell lineages, easy collection procedure, immuno-privileged status, nontumorigenic properties along with minor ethical issues make them an ideal approach for tissue repair. Besides, the number of WJ-MSCs in the umbilical cord samples is high as compared to other sources. Because of these properties, WJ-MSCs have rapidly advanced into clinical trials for the treatment of a wide range of disorders. Therefore, this paper summarized the current preclinical and clinical studies performed to investigate the regenerative potential of WJ-MSCs in neural, myocardial, skin, liver, kidney, cartilage, bone, muscle, and other tissue injuries.
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Affiliation(s)
- Hossein Abbaszadeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Ghorbani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Derakhshani
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Ali Akbar Movassaghpour
- Hematology and Oncology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Yousefi
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mehdi Talebi
- Department of Applied Cell Sciences, School of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Karim Shamsasenjan
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
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24
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Ledesma-Martínez E, Mendoza-Núñez VM, Santiago-Osorio E. Mesenchymal Stem Cells for Periodontal Tissue Regeneration in Elderly Patients. J Gerontol A Biol Sci Med Sci 2020; 74:1351-1358. [PMID: 30289440 DOI: 10.1093/gerona/gly227] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Indexed: 12/16/2022] Open
Abstract
Mesenchymal stem cell (MSC) grafting is a highly promising alternative strategy for periodontal regeneration in periodontitis, which is one of the primary causes of tooth loss in the elderly. However, aging progressively decreases the proliferative and differentiation potential of MSCs and diminishes their regenerative capacity, which represents a limiting factor for their endogenous use in elderly patients. Therefore, tissue regeneration therapy with MSCs in this age group may require a cellular source without the physiological limitations that MSCs exhibit in aging. In this sense, exogenous or allogeneic MSCs could have a better chance of success in regenerating periodontal tissue in elderly patients. This review examines and synthesizes recent data in support of the use of MSCs for periodontal regenerative therapy in patients. Additionally, we analyze the progress of the therapeutic use of exogenous MSCs in humans.
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Affiliation(s)
- Edgar Ledesma-Martínez
- Haematopoiesis and Leukaemia Laboratory, Research Unit on Cell Differentiation and Cancer, National Autonomous University of Mexico, Mexico City, Mexico
| | | | - Edelmiro Santiago-Osorio
- Haematopoiesis and Leukaemia Laboratory, Research Unit on Cell Differentiation and Cancer, National Autonomous University of Mexico, Mexico City, Mexico
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25
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Hotham WE, Henson FMD. The use of large animals to facilitate the process of MSC going from laboratory to patient-'bench to bedside'. Cell Biol Toxicol 2020; 36:103-114. [PMID: 32206986 PMCID: PMC7196082 DOI: 10.1007/s10565-020-09521-9] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Accepted: 03/03/2020] [Indexed: 12/20/2022]
Abstract
Large animal models have been widely used to facilitate the translation of mesenchymal stem cells (MSC) from the laboratory to patient. MSC, with their multi-potent capacity, have been proposed to have therapeutic benefits in a number of pathological conditions. Laboratory studies allow the investigation of cellular and molecular interactions, while small animal models allow initial 'proof of concept' experiments. Large animals (dogs, pigs, sheep, goats and horses) are more similar physiologically and structurally to man. These models have allowed clinically relevant assessments of safety, efficacy and dosing of different MSC sources prior to clinical trials. In this review, we recapitulate the use of large animal models to facilitate the use of MSC to treat myocardial infarction-an example of one large animal model being considered the 'gold standard' for research and osteoarthritis-an example of the complexities of using different large animal models in a multifactorial disease. These examples show how large animals can provide a research platform that can be used to evaluate the value of cell-based therapies and facilitate the process of 'bench to bedside'.
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Affiliation(s)
- W E Hotham
- Division of Trauma and Orthopaedic Surgery, Cambridge University, Cambridge, UK.
| | - F M D Henson
- Division of Trauma and Orthopaedic Surgery, Cambridge University, Cambridge, UK
- Animal Health Trust, Newmarket, UK
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26
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Kot M, Baj-Krzyworzeka M, Szatanek R, Musiał-Wysocka A, Suda-Szczurek M, Majka M. The Importance of HLA Assessment in "Off-the-Shelf" Allogeneic Mesenchymal Stem Cells Based-Therapies. Int J Mol Sci 2019; 20:E5680. [PMID: 31766164 PMCID: PMC6888380 DOI: 10.3390/ijms20225680] [Citation(s) in RCA: 61] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Revised: 10/31/2019] [Accepted: 11/05/2019] [Indexed: 02/07/2023] Open
Abstract
The need for more effective therapies of chronic and acute diseases has led to the attempts of developing more adequate and less invasive treatment methods. Regenerative medicine relies mainly on the therapeutic potential of stem cells. Mesenchymal stem cells (MSCs), due to their immunosuppressive properties and tissue repair abilities, seem to be an ideal tool for cell-based therapies. Taking into account all available sources of MSCs, perinatal tissues become an attractive source of allogeneic MSCs. The allogeneic MSCs provide "off-the-shelf" cellular therapy, however, their allogenicity may be viewed as a limitation for their use. Moreover, some evidence suggests that MSCs are not as immune-privileged as it was previously reported. Therefore, understanding their interactions with the recipient's immune system is crucial for their successful clinical application. In this review, we discuss both autologous and allogeneic application of MSCs, focusing on current approaches to allogeneic MSCs therapies, with a particular interest in the role of human leukocyte antigens (HLA) and HLA-matching in allogeneic MSCs transplantation. Importantly, the evidence from the currently completed and ongoing clinical trials demonstrates that allogeneic MSCs transplantation is safe and seems to cause no major side-effects to the patient. These findings strongly support the case for MSCs efficacy in treatment of a variety of diseases and their use as an "off-the-shelf" medical product.
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Affiliation(s)
- Marta Kot
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
| | - Monika Baj-Krzyworzeka
- Department of Clinical Immunology, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.B.-K.); (R.S.)
| | - Rafał Szatanek
- Department of Clinical Immunology, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.B.-K.); (R.S.)
| | - Aleksandra Musiał-Wysocka
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
| | - Magdalena Suda-Szczurek
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
| | - Marcin Majka
- Department of Transplantation, Faculty of Medicine, Medical College, Jagiellonian University, Wielicka 265, 30-663 Kraków, Poland; (M.K.); (A.M.-W.); (M.S.-S.)
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Pooria A, Pourya A, Gheini A. Animal- and human-based evidence for the protective effects of stem cell therapy against cardiovascular disorders. J Cell Physiol 2019; 234:14927-14940. [PMID: 30811030 DOI: 10.1002/jcp.28330] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2018] [Revised: 12/06/2018] [Accepted: 01/22/2019] [Indexed: 01/24/2023]
Abstract
The increasing rate of mortality and morbidity because of cardiac diseases has called for efficient therapeutic needs. With the advancement in cell-based therapies, stem cells are abundantly studied in this area. Nearly, all sources of stem cells are experimented to treat cardiac injuries. Tissue engineering has also backed this technique by providing an advantageous platform to improve stem cell therapy. After in vitro studies, primary treatment-based research studies comprise small and large animal studies. Furthermore, these studies are implemented in human models in the form of clinical trials. Purpose of this review is to highlight the animal- and human-based studies, exploiting various stem cell sources, to treat cardiovascular disorders.
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Affiliation(s)
- Ali Pooria
- Department of Cardiology, Lorestan University of Medical Sciences, Khoramabad, Iran
| | - Afsoun Pourya
- Student of Research committee, Tehran University of Medical Sciences, Tehran, Iran
| | - Alireza Gheini
- Department of Cardiology, Lorestan University of Medical Sciences, Khoramabad, Iran
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Abstract
The need to search for new, alternative treatments for various diseases has prompted scientists and physicians to focus their attention on regenerative medicine and broadly understood cell therapies. Currently, stem cells are being investigated for their potentially widespread use in therapies for many untreatable diseases. Nowadays modern treatment strategies willingly use mesenchymal stem cells (MSCs) derived from different sources. Researchers are increasingly aware of the nature of MSCs and new possibilities for their use. Due to their properties, especially their ability to self-regenerate, differentiate into several cell lineages and participate in immunomodulation, MSCs have become a promising tool in developing modern and efficient future treatment strategies. The great potential and availability of MSCs allow for their various clinical applications in the treatment of many incurable diseases. In addition to their many advantages and benefits, there are still questions about the use of MSCs. What are the mechanisms of action of MSCs? How do they reach their destination? Is the clinical use of MSCs safe? These are the main questions that arise regarding MSCs when they are considered as therapeutic tools. The diversity of MSCs, their different clinical applications, and their many traits that have not yet been thoroughly investigated are sources of discussions and controversial opinions about these cells. Here, we reviewed the current knowledge about MSCs in terms of their therapeutic potential, clinical effects and safety in clinical applications.
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Affiliation(s)
- Aleksandra Musiał-Wysocka
- 1 Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland.,Both the authors contributed equally in this article
| | - Marta Kot
- 1 Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland.,Both the authors contributed equally in this article
| | - Marcin Majka
- 1 Department of Transplantation, Jagiellonian University Medical College, Cracow, Poland
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Cellular Therapy for Ischemic Heart Disease: An Update. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1201:195-213. [PMID: 31898788 DOI: 10.1007/978-3-030-31206-0_10] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Ischemic heart disease (IHD), which includes heart failure (HF) induced by heart attack (myocardial infarction, MI), is a significant cause of morbidity and mortality worldwide (Benjamin, et al. Circulation 139:e56-e66, 2019). MI occurs at an alarmingly high rate in the United States (approx. One case every 40 seconds), and the failure to repair damaged myocardium is the leading cause of recurrent heart attacks, heart failure (HF), and death within 5 years of MI (Benjamin, et al. Circulation 139:e56-e66, 2019). At present, HF represents an unmet need with no approved clinical therapies to replace the damaged myocardium. As the population ages, the number of heart failure patients is projected to increase, doubling the annual cost by 2030 (Benjamin, et al. Circulation 139:e56-e66, 2019). In the past decades, stem cell therapy has become a promising strategy for cardiac regeneration. However, stem cell-based therapy yielded modest success in human clinical trials. This chapter examines the types of cells examined in cardiac therapy in the setting of IHD, with a brief introduction to ongoing research aiming at enhancing the therapeutic potential of transplanted cells.
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Cell-Based Therapies for Cardiac Regeneration: A Comprehensive Review of Past and Ongoing Strategies. Int J Mol Sci 2018; 19:ijms19103194. [PMID: 30332812 PMCID: PMC6214096 DOI: 10.3390/ijms19103194] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 10/11/2018] [Accepted: 10/12/2018] [Indexed: 12/20/2022] Open
Abstract
Despite considerable improvements in the treatment of cardiovascular diseases, heart failure (HF) still represents one of the leading causes of death worldwide. Poor prognosis is mostly due to the limited regenerative capacity of the adult human heart, which ultimately leads to left ventricular dysfunction. As a consequence, heart transplantation is virtually the only alternative for many patients. Therefore, novel regenerative approaches are extremely needed, and several attempts have been performed to improve HF patients’ clinical conditions by promoting the replacement of the lost cardiomyocytes and by activating cardiac repair. In particular, cell-based therapies have been shown to possess a great potential for cardiac regeneration. Different cell types have been extensively tested in clinical trials, demonstrating consistent safety results. However, heterogeneous efficacy data have been reported, probably because precise end-points still need to be clearly defined. Moreover, the principal mechanism responsible for these beneficial effects seems to be the paracrine release of antiapoptotic and immunomodulatory molecules from the injected cells. This review covers past and state-of-the-art strategies in cell-based heart regeneration, highlighting the advantages, challenges, and limitations of each approach.
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Lalu MM, Mazzarello S, Zlepnig J, Dong YYR, Montroy J, McIntyre L, Devereaux PJ, Stewart DJ, David Mazer C, Barron CC, McIsaac DI, Fergusson DA. Safety and Efficacy of Adult Stem Cell Therapy for Acute Myocardial Infarction and Ischemic Heart Failure (SafeCell Heart): A Systematic Review and Meta-Analysis. Stem Cells Transl Med 2018; 7:857-866. [PMID: 30255989 PMCID: PMC6265630 DOI: 10.1002/sctm.18-0120] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2018] [Accepted: 07/02/2018] [Indexed: 12/25/2022] Open
Abstract
Preclinical and clinical evidence suggests that mesenchymal stem cells (MSCs) may be beneficial in treating both acute myocardial infarction (AMI) and ischemic heart failure (IHF). However, the safety profile and efficacy of MSC therapy is not well‐known. We conducted a systematic review of clinical trials that evaluated the safety or efficacy of MSCs for AMI or IHF. Embase, PubMed/Medline, and Cochrane Central Register of Controlled Trials were searched from inception to September 27, 2017. Studies that examined the use of MSCs administered to adults with AMI or IHF were eligible. The Cochrane risk of bias tool was used to assess bias of included studies. The primary outcome was safety assessed by adverse events and the secondary outcome was efficacy which was assessed by mortality and left ventricular ejection fraction (LVEF). A total of 668 citations were reviewed and 23 studies met eligibility criteria. Of these, 11 studies evaluated AMI and 12 studies evaluated IHF. There was no association between MSCs and acute adverse events. There was a significant improvement in overall LVEF in patients who received MSCs (SMD 0.73, 95% CI 0.24–1.21). No significant difference in mortality was noted (Peto OR 0.68, 95% CI 0.38–1.22). Results from our systematic review suggest that MSC therapy for ischemic heart disease appears to be safe. There is a need for a well‐designed adequately powered randomized control trial (with rigorous adverse event reporting and evaluations of cardiac function) to further establish a clear risk‐benefit profile of MSCs. Stem Cells Translational Medicine2018;7:857–866
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Affiliation(s)
- Manoj M Lalu
- Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.,Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - Sasha Mazzarello
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Jennifer Zlepnig
- Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | | | - Joshua Montroy
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Lauralyn McIntyre
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Division of Critical Care, The Ottawa Hospital, Ottawa, Ontario, Canada
| | - P J Devereaux
- Population Health Research Institute, David Braley Cardiac, Vascular, and Stroke Research Institute, Departments of Medicine and Research Methods, Evidence, and Impact, McMaster University, Hamilton, Ontario, Canada
| | - Duncan J Stewart
- Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada
| | - C David Mazer
- Department of Anesthesia, Li Ka Shing Knowledge Institute of St. Michael's Hospital, University of Toronto, Department of Physiology, Toronto, Ontario, Canada
| | - Carly C Barron
- Department of Medicine, McMaster University, Hamilton, Ontario, Canada
| | - Daniel I McIsaac
- Department of Anesthesiology and Pain Medicine, The Ottawa Hospital, Ottawa, Ontario, Canada.,Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Dean A Fergusson
- Blueprint Translational Research Group, Clinical Epidemiology Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada.,Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada
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Chmiel J, Książek MK, Stryszak W, Iwaszczuk P, Hołda MK, Świtacz G, Kozanecki A, Wilkołek P, Rubiś P, Kopeć G, Odrowąż-Pieniążek P, Przewłocki T, Tracz W, Podolec P, Musiałek P. Temporal changes in the pattern of invasive angiography use and its outcome in suspected coronary artery disease: implications for patient management and healthcare resources utilization. ADVANCES IN INTERVENTIONAL CARDIOLOGY 2018; 14:247-257. [PMID: 30302100 PMCID: PMC6173087 DOI: 10.5114/aic.2018.78327] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2018] [Accepted: 09/04/2018] [Indexed: 12/18/2022] Open
Abstract
INTRODUCTION Invasive coronary angiography (CAG), the 'gold standard' in coronary artery disease (CAD) diagnosis, requires hospitalization, is not risk-free, and engages considerable healthcare resources. AIM To assess recent (throught out 10 years) evolution of 'significant' (≥ 50% stenosis(es)) CAD prevalence in subjects undergoing CAG for CAD diagnosis in a high-volume tertiary referral center. MATERIAL AND METHODS Anonymized medical records were compared for the last vs. the first 2-years of the decade (June 2007 to May 2018). Referrals for suspected CAD were 2067 of 4522 hospitalizations (45.7%) and 1755 of 5196 (33.8%) respectively (p < 0.001). RESULTS The median patient age (64 vs. 68 years) and the prevalence of heart failure (24.1% vs. 42.2%) increased significantly (p < 0.001). The CAG atherosclerotic lesions, for all stenosis categories (< 50%; ≥ 50%; ≥ 70%; occlusion(s)), were significantly more prevalent in men. The proportion of subjects with any atherosclerosis on CAG increased (80.7% vs. 77.6%, p = 0.015). However, in the absence of any gross change in, for instance, the fraction of women (40.4% vs. 41.8%), the proportion of CAGs with significant CAD (lesion(s) ≥ 50%) decreased from 55.2% in 2007/2008 to below 1 in every 2 angiograms (48.9%) in 2017/2018 (p < 0.001). This unexpected finding occurred consistently across nearly all CAG referral categories. CONCLUSIONS Despite more advanced age and a higher proportion of subjects with 'any' coronary atherosclerosis on CAG, the likelihood of a 'negative' angiogram (lesion(s) < 50%; no further evaluation/intervention) has increased significantly over the last decade. The exact nature of this phenomenon requires further investigation, particularly as a reverse trend would be expected with the growing role (and current high penetration) of contemporary non-invasive diagnostic tools to rule out significant CAD.
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Affiliation(s)
- Jakub Chmiel
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Miłosz K. Książek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Weronika Stryszak
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Paweł Iwaszczuk
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Mateusz K. Hołda
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
- HEART – Heart Embryology and Anatomy Research Team, Department of Anatomy, Jagiellonian University Medical College, Kraków, Poland
| | - Grażyna Świtacz
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Artur Kozanecki
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Piotr Wilkołek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Paweł Rubiś
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Grzegorz Kopeć
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Piotr Odrowąż-Pieniążek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Tadeusz Przewłocki
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Wiesława Tracz
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Piotr Podolec
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
| | - Piotr Musiałek
- Department of Cardiac and Vascular Diseases, Jagiellonian University, John Paul II Hospital, Kraków, Poland
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Kobayashi K, Suzuki K. Mesenchymal Stem/Stromal Cell-Based Therapy for Heart Failure ― What Is the Best Source? ―. Circ J 2018; 82:2222-2232. [DOI: 10.1253/circj.cj-18-0786] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Affiliation(s)
- Kazuya Kobayashi
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
| | - Ken Suzuki
- William Harvey Research Institute, Barts and The London School of Medicine, Queen Mary University of London
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Hernández-Monjaraz B, Santiago-Osorio E, Ledesma-Martínez E, Alcauter-Zavala A, Mendoza-Núñez VM. Retrieval of a periodontally compromised tooth by allogeneic grafting of mesenchymal stem cells from dental pulp: A case report. J Int Med Res 2018; 46:2983-2993. [PMID: 29911458 PMCID: PMC6124270 DOI: 10.1177/0300060518773244] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Objective To report a case of successful allogeneic grafting of mesenchymal dental pulp stem cells (DPSCs) as preliminary findings in a patient with periodontal disease enrolled into clinical trial ISRCTN12831118. Methods Mesenchymal stem cells from the dental pulp of a deciduous tooth from a 7-year-old donor were separated from the pulp chamber and processed via enzymatic digestion and centrifugation. DPSCs were passaged and cultured on a 35 × 13 mm culture dish in minimum essential medium-alpha, without supplementation. After reaching 80% confluency, 5 x 106 allogeneic DPSCs in 250 µl phosphate buffered saline were seeded onto a dry scaffold of lyophilized collagen-polyvinylpyrrolidone sponge placed in the left lower premolar area of a 61-year-old patient with periodontal disease. Surgical access to the lower premolar area was achieved using the flap technique. Results At 3 and 6 months following allogeneic graft, the patient showed no sign of rejection and exhibited decreases in tooth mobility, periodontal pocket depth and bone defect area. Bone mineral density had increased at the graft site. Conclusions Regenerative periodontal therapy using DPSCs of allogeneic origin may be a promising treatment for periodontal disease-induced bone defects.
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Affiliation(s)
- Beatriz Hernández-Monjaraz
- 1 Research Unit on Gerontology, FES Zaragoza, National Autonomous University of Mexico, Mexico City, Mexico
| | - Edelmiro Santiago-Osorio
- 2 Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, Mexico City, Mexico
| | - Edgar Ledesma-Martínez
- 2 Hematopoiesis and Leukemia Laboratory, Research Unit on Cell Differentiation and Cancer, FES Zaragoza, National Autonomous University of Mexico, Mexico City, Mexico
| | - Andrés Alcauter-Zavala
- 1 Research Unit on Gerontology, FES Zaragoza, National Autonomous University of Mexico, Mexico City, Mexico
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Majka M, Sułkowski M, Badyra B, Musiałek P. Concise Review: Mesenchymal Stem Cells in Cardiovascular Regeneration: Emerging Research Directions and Clinical Applications. Stem Cells Transl Med 2017; 6:1859-1867. [PMID: 28836732 PMCID: PMC6430161 DOI: 10.1002/sctm.16-0484] [Citation(s) in RCA: 87] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2016] [Accepted: 07/18/2017] [Indexed: 12/26/2022] Open
Abstract
Experimental and early clinical data suggest that, due to several unique properties, mesenchymal stem cells (MSCs) may be more effective than other cell types for diseases that are difficult to treat or untreatable. Owing to their ease of isolation and culture as well as their secretory and immunomodulatory abilities, MSCs are the most promising option in the field of cell-based therapies. Although MSCs from various sources share several common characteristics, they also exhibit several important differences. These variations may reflect, in part, specific regional properties of the niches from which the cells originate. Moreover, morphological and functional features of MSCs are susceptible to variations across isolation protocols and cell culture conditions. These observations suggest that careful preparation of manufacturing protocols will be necessary for the most efficient use of MSCs in future clinical trials. A typical human myocardial infarct involves the loss of approximately 1 billion cardiomyocytes and 2-3 billion other (mostly endothelial) myocardial cells, leading (despite maximized medical therapy) to a significant negative impact on the length and quality of life. Despite more than a decade of intensive research, search for the "best" (safe and maximally effective) cell type to drive myocardial regeneration continues. In this review, we summarize information about the most important features of MSCs and recent discoveries in the field of MSCs research, and describe current data from preclinical and early clinical studies on the use of MSCs in cardiovascular regeneration. Stem Cells Translational Medicine 2017;6:1859-1867.
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Affiliation(s)
- Marcin Majka
- Department of TransplantationJagiellonian University Medical CollegeKrakowPoland
| | - Maciej Sułkowski
- Department of TransplantationJagiellonian University Medical CollegeKrakowPoland
| | - Bogna Badyra
- Department of TransplantationJagiellonian University Medical CollegeKrakowPoland
| | - Piotr Musiałek
- Department of Cardiac & Vascular Diseases, John Paul II HospitalJagiellonian UniversityKrakowPoland
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Crosstalk between mesenchymal stem cells and macrophages in inflammatory bowel disease and associated colorectal cancer. Contemp Oncol (Pozn) 2017; 21:91-97. [PMID: 28947877 PMCID: PMC5611497 DOI: 10.5114/wo.2017.68616] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2017] [Accepted: 05/17/2017] [Indexed: 12/19/2022] Open
Abstract
Mesenchymal stem cells (MSCs) are attractive seed cells for immunotherapy, tissue engineering and regenerative medicine due to their self-renewal and multidirectional differentiation abilities, diverse immunoregulatory functions and ease of isolation from a wide range of tissues. MSCs exert their immunoregulatory effect on immune cells via cell-to-cell contact and paracrine mechanisms. In turn, MSCs can also be modulated by immune cells. Macrophages are constantly present in the mucosa of the intestinal tract of mammals and play an important role in the development and progression of inflammatory bowel disease (IBD), a chronic and recurrent inflammatory disease of the gastrointestinal tract characterized by idiopathic mucosal inflammation. The increased morbidity and mortality of IBD have made it a disease hard to cure in the clinic. MSCs have emerged as an important tool for IBD therapy due to their abilities to differentiate into enterocyte-like cells and regulate inflammatory cells, especially macrophages. In this review, we discuss the recent advances in the interaction between MSCs and macrophages in diseases, with an emphasis on IBD. We propose that an optimized MSC-based therapy would provide a novel strategy for the treatment of IBD and the prevention of IBD-associated colorectal cancer (CRC).
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Gaafar T, Attia W, Mahmoud S, Sabry D, Aziz OA, Rasheed D, Hamza H. Cardioprotective Effects of Wharton Jelly Derived Mesenchymal Stem Cell Transplantation in a Rodent Model of Myocardial Injury. Int J Stem Cells 2017; 10:48-59. [PMID: 28446005 PMCID: PMC5488776 DOI: 10.15283/ijsc16063] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/04/2017] [Indexed: 01/03/2023] Open
Abstract
Background Whartons jelly-derived mesenchymal stem cells are a valuable alternative source that possess multipotent properties, easy to obtain and available in large scale compared to BMMSCs. We investigated the possibility of cardiac function improvement post isoproterenol induced cardiac injury in a rat model following human WJMSCs transplantation. Materials and Methods MSCs were extracted and cultured from cord WJ, characterized by morphology, Immunophenotyping and differentiation to osteoblast and adipocytes. WJMSCs were labeled with PKH2 linker dye. Wistar rats were divided into control group, ISO group (injected with 2 doses of isoproterenol) to induce myocardial injury and ISO group transplanted with labelled WJMSCs. ECG, electrocardiographic patterns, cardiac marker enzymes, tracing of labeled MSCs and immunohistochemical analysis of myocardial cryosections were studied. Results and Conclusions WJ derived MSCs were expanded for more than 14 passages while maintaining their undifferentiated state, were positive for MSC markers and were able to differentiate into adipocyte and osteoblast. We demonstrated that intravenously administered WJMSCs were capable of homing predominently in the ischemic myocardium. Cardiac markers were positively altered in stem cell treated group compared to ISO group. ECG and ECHO changes were improved with higher survival rate. WJMSCs could differentiate into cardiac-like cells (positive for cardiac specific proteins) in vivo. WJMSCs infusion promoted cardiac protection and reduced mortality, emphasizing a promising therapeutic role for myocardial insufficiency.
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Affiliation(s)
- Taghrid Gaafar
- Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Wael Attia
- Department of Pediatric Cardiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Shereen Mahmoud
- Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Dina Sabry
- Department of Biochemistry, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Osama Abdel Aziz
- Department of Pediatric Cardiology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Dina Rasheed
- Department of Clinical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
| | - Hala Hamza
- Department of Pediatric Cardiology, Faculty of Medicine, Cairo University, Cairo, Egypt
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Singh A, Singh A, Sen D. Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015). Stem Cell Res Ther 2016; 7:82. [PMID: 27259550 PMCID: PMC4893234 DOI: 10.1186/s13287-016-0341-0] [Citation(s) in RCA: 154] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed.
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Affiliation(s)
- Aastha Singh
- School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Abhishek Singh
- School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Dwaipayan Sen
- School of Bio Sciences and Technology, VIT University, Vellore, India. .,Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), VIT University, Vellore, 632014, Tamil Nadu, India.
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