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1
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Shah S, Nawaz HS, Qazi MS, Jain H, Lucke-Wold B. Living biodrugs and how tissue source influences mesenchymal stem cell therapeutics for heart failure. World J Cardiol 2024; 16:619-625. [PMID: 39600993 PMCID: PMC11586726 DOI: 10.4330/wjc.v16.i11.619] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Revised: 09/21/2024] [Accepted: 10/20/2024] [Indexed: 10/30/2024] Open
Abstract
In this editorial we comment on the article by Safwan M et al. We especially focused on the cardiac function restoration by the use of mesenchymal stem cells (MSCs) therapy for heart failure (HF), which has emerged as a new treatment approach as "Living Biodrugs". HF remains a significant clinical challenge due to the heart's inability to pump blood effectively, despite advancements in medical and device-based therapies. MSCs have emerged as a promising therapeutic approach, offering benefits beyond traditional treatments through their ability to modulate inflammation, reduce fibrosis, and promote endogenous tissue regeneration. MSCs can be derived from various tissues, including bone marrow and umbilical cord. Umbilical cord-derived MSCs exhibit superior expansion capabilities, making them an attractive option for HF therapy. Conversely, bone marrow-derived MSCs have been extensively studied for their potential to improve cardiac function but face challenges related to cell retention and delivery. Future research is focusing on optimizing MSC sources, enhancing differentiation and immune modulation, and improving delivery methods to overcome current limitations.
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Affiliation(s)
- Siddharth Shah
- Lillian S Wells Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States.
| | - Huzaifa Sabir Nawaz
- Department of Internal Medicine, Services Institute of Medical Sciences, Lahore 54000, Pakistan
| | - Muhammad Saeed Qazi
- Department of Internal Medicine, Bilawal Medical College for Boys, Jamshoro 54000, Pakistan
| | - Hritvik Jain
- Department of Internal Medicine, All India Institute of Medical Sciences, Jodhpur 400022, India
| | - Brandon Lucke-Wold
- Lillian S Wells Department of Neurosurgery, University of Florida, Gainesville, FL 32608, United States
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2
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Haider KH. Priming mesenchymal stem cells to develop "super stem cells". World J Stem Cells 2024; 16:623-640. [PMID: 38948094 PMCID: PMC11212549 DOI: 10.4252/wjsc.v16.i6.623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2024] [Revised: 05/04/2024] [Accepted: 05/20/2024] [Indexed: 06/25/2024] Open
Abstract
The stem cell pre-treatment approaches at cellular and sub-cellular levels encompass physical manipulation of stem cells to growth factor treatment, genetic manipulation, and chemical and pharmacological treatment, each strategy having advantages and limitations. Most of these pre-treatment protocols are non-combinative. This editorial is a continuum of Li et al's published article and Wan et al's editorial focusing on the significance of pre-treatment strategies to enhance their stemness, immunoregulatory, and immunosuppressive properties. They have elaborated on the intricacies of the combinative pre-treatment protocol using pro-inflammatory cytokines and hypoxia. Applying a well-defined multi-pronged combinatorial strategy of mesenchymal stem cells (MSCs), pre-treatment based on the mechanistic understanding is expected to develop "Super MSCs", which will create a transformative shift in MSC-based therapies in clinical settings, potentially revolutionizing the field. Once optimized, the standardized protocols may be used with slight modifications to pre-treat different stem cells to develop "super stem cells" with augmented stemness, functionality, and reparability for diverse clinical applications with better outcomes.
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Affiliation(s)
- Khawaja Husnain Haider
- Department of Basic Sciences, Sulaiman AlRajhi University, AlQaseem 52736, Saudi Arabia.
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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: 4] [Impact Index Per Article: 4.0] [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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4
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Yamada S, Bartunek J, Povsic TJ, Cotter G, Davison BA, Edwards C, Behfar A, Metra M, Filippatos GS, Vanderheyden M, Wijns W, Terzic A. Cell Therapy Improves Quality-of-Life in Heart Failure: Outcomes From a Phase III Clinical Trial. Stem Cells Transl Med 2024; 13:116-124. [PMID: 38006196 PMCID: PMC10872684 DOI: 10.1093/stcltm/szad078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 10/13/2023] [Indexed: 11/26/2023] Open
Abstract
Patients with heart failure experience limitations in daily activity and poor quality-of-life. Prospective surveillance of health-related quality-of-life supplemented traditional death and hospitalization outcomes in the multinational, randomized, double-blinded CHART-1 clinical trial that assessed cardiopoiesis-guided cell therapy in ischemic heart failure patients with reduced left ventricular ejection fraction. The Minnesota Living with Heart Failure Questionnaire (MLHFQ), a Food and Drug Administration qualified instrument for evaluating therapeutic effectiveness, was applied through the 1-year follow-up. Cell treated (n = 109) and sham procedure (n = 140) cohorts reported improved MLHFQ scores comparable between the 2 study arms (mean treatment difference with baseline adjustment -3.2 points, P = .107). Superiority of cell treatment over sham in betterment of the MLHFQ score was demonstrated in patients with pre-existing advanced left ventricular enlargement (baseline-adjusted mean treatment difference -6.4 points, P = .009). In this highly responsive subpopulation, benefit on the MLHFQ score paralleled reduction in death and hospitalization post-cell therapy (adjusted Mann-Whitney odds 1.43, 95% CI, 1.01-2.01; P = .039). The potential of cell therapy in addressing the quality-of-life dimension of heart failure requires further evaluation for disease relief.
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Affiliation(s)
- Satsuki Yamada
- Department of Cardiovascular Medicine, Center for Regenerative Medicine, Marriott Heart Disease Research Program, Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN, USA
| | | | - Thomas J Povsic
- Program for Advanced Coronary Disease, Duke Clinical Research Institute and Duke University Medical Center, Durham, NC, USA
| | - Gad Cotter
- Momentum Research, Inc., Durham, NC, USA
- Université Paris Cité; Inserm UMR-S 942, MASCOT, Paris, France
| | - Beth A Davison
- Momentum Research, Inc., Durham, NC, USA
- Université Paris Cité; Inserm UMR-S 942, MASCOT, Paris, France
| | | | - Atta Behfar
- Department of Cardiovascular Medicine, Center for Regenerative Medicine, Marriott Heart Disease Research Program, Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN, USA
- Department of Physiology & Biomedical Engineering, Mayo Clinic, Rochester, MN, USA
| | - Marco Metra
- Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Spedali Civili, Brescia, Italy
| | - Gerasimos S Filippatos
- Department of Cardiology, National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece
| | | | - William Wijns
- The Lambe Institute for Translational Medicine, the Smart Sensors Laboratory and CURAM, University of Galway, Galway, Ireland
| | - Andre Terzic
- Department of Cardiovascular Medicine, Center for Regenerative Medicine, Marriott Heart Disease Research Program, Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology & Experimental Therapeutics, Department of Clinical Genomics, Mayo Clinic, Rochester, MN, USA
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5
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Zhang R, Duan X, Liu Y, Xu J, Al-bashari AAG, Ye P, Ye Q, He Y. The Application of Mesenchymal Stem Cells in Future Vaccine Synthesis. Vaccines (Basel) 2023; 11:1631. [PMID: 38005963 PMCID: PMC10675160 DOI: 10.3390/vaccines11111631] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2023] [Revised: 10/09/2023] [Accepted: 10/20/2023] [Indexed: 11/26/2023] Open
Abstract
Vaccines have significant potential in treating and/or preventing diseases, yet there remain challenges in developing effective vaccines against some diseases, such as AIDS and certain tumors. Mesenchymal stem cells (MSCs), a subset of cells with low immunogenicity, high proliferation potential, and an abundant source of extracellular vesicles (EVs), represent one of the novel and promising vaccine platforms. This review describes the unique features and potential mechanisms of MSCs as a novel vaccine platform. We also cover aspects such as the safety and stability of MSCs that warrant future in-depth studies.
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Affiliation(s)
- Rui Zhang
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Xingxiang Duan
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Ye Liu
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Jia Xu
- Australian Rivers Institute and School of Environment and Science, Griffith University, Nathan, QLD 4111, Australia;
| | - Abdullkhaleg Ali Ghaleb Al-bashari
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Peng Ye
- Department of Pharmacy, Renmin Hospital of Wuhan University, Wuhan 430060, China;
| | - Qingsong Ye
- Center of Regenerative Medicine & Department of Stomatology, Renmin Hospital of Wuhan University, Wuhan 430060, China; (R.Z.); (X.D.); (Y.L.); (A.A.G.A.-b.)
| | - Yan He
- Institute of Regenerative and Translational Medicine, Department of Stomatology, Tianyou Hospital, Wuhan University of Science and Technology, Wuhan 430030, China
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6
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Bartunek J, Terzic A. Optimized Catheter System Demonstrates Utility for Endomyocardial Delivery of Cardiopoietic Stem Cells in Target Patients With Heart Failure. Tex Heart Inst J 2023; 50:e238247. [PMID: 37881036 PMCID: PMC10658137 DOI: 10.14503/thij-23-8247] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2023]
Affiliation(s)
- Jozef Bartunek
- Cardiovascular Center, Onze-Lieve-Vrouwziekenhuis Hospital, Aalst, Belgium
| | - Andre Terzic
- Marriott Heart Disease Research Program, Center for Regenerative Medicine and Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota
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7
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Li K, Zhu Z, Sun X, Zhao L, Liu Z, Xing J. Harnessing the therapeutic potential of mesenchymal stem cell-derived exosomes in cardiac arrest: Current advances and future perspectives. Biomed Pharmacother 2023; 165:115201. [PMID: 37480828 DOI: 10.1016/j.biopha.2023.115201] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2023] [Revised: 07/16/2023] [Accepted: 07/18/2023] [Indexed: 07/24/2023] Open
Abstract
BACKGROUND Cardiac arrest (CA), characterized by sudden onset and high mortality rates, is one of the leading causes of death globally, with a survival rate of approximately 6-24%. Studies suggest that the restoration of spontaneous circulation (ROSC) hardly improved the mortality rate and prognosis of patients diagnosed with CA, largely due to ischemia-reperfusion injury. MAIN BODY Mesenchymal stem cells (MSCs) exhibit self-renewal and strong potential for multilineage differentiation. Their effects are largely mediated by extracellular vesicles (EVs). Exosomes are the most extensively studied subgroup of EVs. EVs mainly mediate intercellular communication by transferring vesicular proteins, lipids, nucleic acids, and other substances to regulate multiple processes, such as cytokine production, cell proliferation, apoptosis, and metabolism. Thus, exosomes exhibit significant potential for therapeutic application in wound repair, tissue reconstruction, inflammatory reaction, and ischemic diseases. CONCLUSION Based on similar pathological mechanisms underlying post-cardiac arrest syndrome involving various tissues and organs in many diseases, the review summarizes the therapeutic effects of MSC-derived exosomes and explores the prospects for their application in the treatment of CA.
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Affiliation(s)
- Ke Li
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
| | - Zhu Zhu
- Department of Breast Surgery, General Surgery Center, The First Hospital of Jilin University, Changchun 130021, China.
| | - Xiumei Sun
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
| | - Linhong Zhao
- Northeast Normal University, Changchun 130022, China.
| | - Zuolong Liu
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
| | - Jihong Xing
- Department of Emergency Medicine, The First Hospital of Jilin University, Changchun 130021, China.
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8
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Zhuo D, Lei I, Li W, Liu L, Li L, Ni J, Liu Z, Fan G. The origin, progress, and application of cell-based cardiac regeneration therapy. J Cell Physiol 2023; 238:1732-1755. [PMID: 37334836 DOI: 10.1002/jcp.31060] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2023] [Revised: 05/08/2023] [Accepted: 05/29/2023] [Indexed: 06/21/2023]
Abstract
Cardiovascular disease (CVD) has become a severe threat to human health, with morbidity and mortality increasing yearly and gradually becoming younger. When the disease progresses to the middle and late stages, the loss of a large number of cardiomyocytes is irreparable to the body itself, and clinical drug therapy and mechanical support therapy cannot reverse the development of the disease. To explore the source of regenerated myocardium in model animals with the ability of heart regeneration through lineage tracing and other methods, and develop a new alternative therapy for CVDs, namely cell therapy. It directly compensates for cardiomyocyte proliferation through adult stem cell differentiation or cell reprogramming, which indirectly promotes cardiomyocyte proliferation through non-cardiomyocyte paracrine, to play a role in heart repair and regeneration. This review comprehensively summarizes the origin of newly generated cardiomyocytes, the research progress of cardiac regeneration based on cell therapy, the opportunity and development of cardiac regeneration in the context of bioengineering, and the clinical application of cell therapy in ischemic diseases.
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Affiliation(s)
- Danping Zhuo
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Ienglam Lei
- Department of Cardiac Surgery, Frankel Cardiovascular Center, University of Michigan, Ann Arbor, Michigan, USA
| | - Wenjun Li
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Li Liu
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Lan Li
- State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Jingyu Ni
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Zhihao Liu
- State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
| | - Guanwei Fan
- National Clinical Research Center for Chinese Medicine Acupuncture and Moxibustion, First Teaching Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, China
- State Key Laboratory of Modern Chinese Medicine, Key Laboratory of Pharmacology of Traditional Chinese Medical Formulae, Ministry of Education, Tianjin University of Traditional Chinese Medicine, Tianjin, China
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9
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Suhar RA, Doulames VM, Liu Y, Hefferon ME, Figueroa O, Buabbas H, Heilshorn SC. Hyaluronan and elastin-like protein (HELP) gels significantly improve microsphere retention in the myocardium. Biomater Sci 2022; 10:2590-2608. [PMID: 35411353 PMCID: PMC9123900 DOI: 10.1039/d1bm01890f] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2023]
Abstract
Heart disease is the leading cause of death globally, and delivery of therapeutic cargo (e.g., particles loaded with proteins, drugs, or genes and cells) through direct injection into the myocardium is a promising clinical intervention. However, retention of deliverables to the contracting myocardium is low, with as much as 60-90% of payload being lost within 24 hr. Commercially-available injectable hydrogels, including Matrigel, have been hypothesized to increase payload retention but have not yielded significant improvements in quantified analyses. Here, we assess a recombinant hydrogel composed of chemically modified hyaluronan and elastin-like protein (HELP) as an alternative injectable carrier to increase cargo retention. HELP is crosslinked using dynamic covalent bonds, and tuning the hyaluronan chemistry significantly alters hydrogel mechanical properties including stiffness, stress relaxation rate, and ease of injectability through a needle or catheter. These materials can be injected even after complete crosslinking, extending the time window for surgical delivery. We show that HELP gels significantly improve in vivo retention of microsphere cargo compared to Matrigel, both 1 day and 7 days post-injection directly into the rat myocardium. These data suggest that HELP gels may assist with the clinical translation of therapeutic cargo designed for delivery into the contracting myocardium by preventing acute cargo loss.
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Affiliation(s)
- Riley A Suhar
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
| | - Vanessa M Doulames
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Yueming Liu
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
| | - Meghan E Hefferon
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, California 94305, USA
| | | | - Hana Buabbas
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
- Department of Biology, Stanford University, Stanford, California, 94305, USA
| | - Sarah C Heilshorn
- Department of Materials Science and Engineering, Stanford University, Stanford, California 94305, USA.
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10
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Sarre C, Contreras-Lopez R, Nernpermpisooth N, Barrere C, Bahraoui S, Terraza C, Tejedor G, Vincent A, Luz-Crawford P, Kongpol K, Kumphune S, Piot C, Nargeot J, Jorgensen C, Djouad F, Barrere-Lemaire S. PPARβ/δ priming enhances the anti-apoptotic and therapeutic properties of mesenchymal stromal cells in myocardial ischemia-reperfusion injury. Stem Cell Res Ther 2022; 13:167. [PMID: 35461240 PMCID: PMC9034535 DOI: 10.1186/s13287-022-02840-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2021] [Accepted: 03/25/2022] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Mesenchymal Stromal Cells (MSC) have been widely used for their therapeutic properties in many clinical applications including myocardial infarction. Despite promising preclinical results and evidences of safety and efficacy in phases I/ II, inconsistencies in phase III trials have been reported. In a previous study, we have shown using MSC derived from the bone marrow of PPARβ/δ (Peroxisome proliferator-activated receptors β/δ) knockout mice that the acute cardioprotective properties of MSC during the first hour of reperfusion are PPARβ/δ-dependent but not related to the anti-inflammatory effect of MSC. However, the role of the modulation of PPARβ/δ expression on MSC cardioprotective and anti-apoptotic properties has never been investigated. OBJECTIVES The aim of this study was to investigate the role of PPARβ/δ modulation (inhibition or activation) in MSC therapeutic properties in vitro and ex vivo in an experimental model of myocardial infarction. METHODS AND RESULTS Naïve MSC and MSC pharmacologically activated or inhibited for PPARβ/δ were challenged with H2O2. Through specific DNA fragmentation quantification and qRT-PCR experiments, we evidenced in vitro an increased resistance to oxidative stress in MSC pre-treated by the PPARβ/δ agonist GW0742 versus naïve MSC. In addition, PPARβ/δ-priming allowed to reveal the anti-apoptotic effect of MSC on cardiomyocytes and endothelial cells in vitro. When injected during reperfusion, in an ex vivo heart model of myocardial infarction, 3.75 × 105 PPARβ/δ-primed MSC/heart provided the same cardioprotective efficiency than 7.5 × 105 naïve MSC, identified as the optimal dose in our experimental model. This enhanced short-term cardioprotective effect was associated with an increase in both anti-apoptotic effects and the number of MSC detected in the left ventricular wall at 1 h of reperfusion. By contrast, PPARβ/δ inhibition in MSC before their administration in post-ischemic hearts during reperfusion decreased their cardioprotective effects. CONCLUSION Altogether these results revealed that PPARβ/δ-primed MSC exhibit an increased resistance to oxidative stress and enhanced anti-apoptotic properties on cardiac cells in vitro. PPARβ/δ-priming appears as an innovative strategy to enhance the cardioprotective effects of MSC and to decrease the therapeutic injected doses. These results could be of major interest to improve MSC efficacy for the cardioprotection of injured myocardium in AMI patients.
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Affiliation(s)
- Charlotte Sarre
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France.,IRMB, Univ Montpellier, INSERM, Montpellier, France
| | - Rafael Contreras-Lopez
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France.,IRMB, Univ Montpellier, INSERM, Montpellier, France
| | - Nitirut Nernpermpisooth
- IBRU, Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
| | - Christian Barrere
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France
| | | | | | | | - Anne Vincent
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France
| | - Patricia Luz-Crawford
- Laboratorio de Inmunología Celular y Molecular, Facultad de Medicina, Universidad de los Andes, Santiago, Chile.,IMPACT, Center of Interventional Medicine for Precision and Advanced Cellular Therapy, Santiago, Chile
| | - Kantapich Kongpol
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France.,IBRU, Department of Cardio-Thoracic Technology, Faculty of Allied Health Sciences, Naresuan University, Phitsanulok, Thailand
| | - Sarawut Kumphune
- School of Allied Health Sciences, Walailak University, Nakhon Si Thammarat, Thailand
| | - Christophe Piot
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France.,Département de Cardiologie Interventionnelle, Clinique du Millénaire, Montpellier, France
| | - Joel Nargeot
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France
| | - Christian Jorgensen
- IRMB, Univ Montpellier, INSERM, Montpellier, France.,CHU Montpellier, 34295, Montpellier, France
| | - Farida Djouad
- IRMB, Univ Montpellier, INSERM, Montpellier, France.
| | - Stéphanie Barrere-Lemaire
- IGF, Université de Montpellier, CNRS, INSERM, 141 rue de la Cardonille, 34094, Montpellier Cedex 5, France.
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11
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Liu Y, Schwam J, Chen Q. Senescence-Associated Cell Transition and Interaction (SACTAI): A Proposed Mechanism for Tissue Aging, Repair, and Degeneration. Cells 2022; 11:1089. [PMID: 35406653 PMCID: PMC8997723 DOI: 10.3390/cells11071089] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2022] [Revised: 03/21/2022] [Accepted: 03/22/2022] [Indexed: 02/01/2023] Open
Abstract
Aging is a broad process that occurs as a time-dependent functional decline and tissue degeneration in living organisms. On a smaller scale, aging also exists within organs, tissues, and cells. As the smallest functional unit in living organisms, cells "age" by reaching senescence where proliferation stops. Such cellular senescence is achieved through replicative stress, telomere erosion and stem cell exhaustion. It has been shown that cellular senescence is key to tissue degradation and cell death in aging-related diseases (ARD). However, senescent cells constitute only a small percentage of total cells in the body, and they are resistant to death during aging. This suggests that ARD may involve interaction of senescent cells with non-senescent cells, resulting in senescence-triggered death of non-senescent somatic cells and tissue degeneration in aging organs. Here, based on recent research evidence from our laboratory and others, we propose a mechanism-Senescence-Associated Cell Transition and Interaction (SACTAI)-to explain how cell heterogeneity arises during aging and how the interaction between somatic cells and senescent cells, some of which are derived from aging somatic cells, results in cell death and tissue degeneration.
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Affiliation(s)
| | | | - Qian Chen
- Laboratory of Molecular Biology and Nanomedicine, Department of Orthopaedics, Alpert Medical School of Brown University, Rhode Island Hospital, Providence, RI 02903, USA; (Y.L.); (J.S.)
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12
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Do the Current Guidelines for Heart Failure Diagnosis and Treatment Fit with Clinical Complexity? J Clin Med 2022; 11:jcm11030857. [PMID: 35160308 PMCID: PMC8836547 DOI: 10.3390/jcm11030857] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/01/2022] [Accepted: 02/04/2022] [Indexed: 02/06/2023] Open
Abstract
Heart failure (HF) is a clinical syndrome defined by specific symptoms and signs due to structural and/or functional heart abnormalities, which lead to inadequate cardiac output and/or increased intraventricular filling pressure. Importantly, HF becomes progressively a multisystemic disease. However, in August 2021, the European Society of Cardiology published the new Guidelines for the diagnosis and treatment of acute and chronic HF, according to which the left ventricular ejection fraction (LVEF) continues to represent the pivotal parameter for HF patients’ evaluation, risk stratification and therapeutic management despite its limitations are well known. Indeed, HF has a complex pathophysiology because it first involves the heart, progressively becoming a multisystemic disease, leading to multiorgan failure and death. In these terms, HF is comparable to cancer. As for cancer, surviving, morbidity and hospitalisation are related not only to the primary neoplastic mass but mainly to the metastatic involvement. In HF, multiorgan involvement has a great impact on prognosis, and multiorgan protective therapies are equally important as conventional cardioprotective therapies. In the light of these considerations, a revision of the HF concept is needed, starting from its definition up to its therapy, to overcome the old and simplistic HF perspective.
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13
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Diaz-Navarro R, Urrútia G, Cleland JG, Poloni D, Villagran F, Acosta-Dighero R, Bangdiwala SI, Rada G, Madrid E. Stem cell therapy for dilated cardiomyopathy. Cochrane Database Syst Rev 2021; 7:CD013433. [PMID: 34286511 PMCID: PMC8406792 DOI: 10.1002/14651858.cd013433.pub2] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
BACKGROUND Stem cell therapy (SCT) has been proposed as an alternative treatment for dilated cardiomyopathy (DCM), nonetheless its effectiveness remains debatable. OBJECTIVES To assess the effectiveness and safety of SCT in adults with non-ischaemic DCM. SEARCH METHODS We searched CENTRAL in the Cochrane Library, MEDLINE, and Embase for relevant trials in November 2020. We also searched two clinical trials registers in May 2020. SELECTION CRITERIA Eligible studies were randomized controlled trials (RCT) comparing stem/progenitor cells with no cells in adults with non-ischaemic DCM. We included co-interventions such as the administration of stem cell mobilizing agents. Studies were classified and analysed into three categories according to the comparison intervention, which consisted of no intervention/placebo, cell mobilization with cytokines, or a different mode of SCT. The first two comparisons (no cells in the control group) served to assess the efficacy of SCT while the third (different mode of SCT) served to complement the review with information about safety and other information of potential utility for a better understanding of the effects of SCT. DATA COLLECTION AND ANALYSIS Two review authors independently screened all references for eligibility, assessed trial quality, and extracted data. We undertook a quantitative evaluation of data using random-effects meta-analyses. We evaluated heterogeneity using the I² statistic. We could not explore potential effect modifiers through subgroup analyses as they were deemed uninformative due to the scarce number of trials available. We assessed the certainty of the evidence using the GRADE approach. We created summary of findings tables using GRADEpro GDT. We focused our summary of findings on all-cause mortality, safety, health-related quality of life (HRQoL), performance status, and major adverse cardiovascular events. MAIN RESULTS We included 13 RCTs involving 762 participants (452 cell therapy and 310 controls). Only one study was at low risk of bias in all domains. There were many shortcomings in the publications that did not allow a precise assessment of the risk of bias in many domains. Due to the nature of the intervention, the main source of potential bias was lack of blinding of participants (performance bias). Frequently, the format of the continuous data available was not ideal for use in the meta-analysis and forced us to seek strategies for transforming data in a usable format. We are uncertain whether SCT reduces all-cause mortality in people with DCM compared to no intervention/placebo (mean follow-up 12 months) (risk ratio (RR) 0.84, 95% confidence interval (CI) 0.54 to 1.31; I² = 0%; studies = 7, participants = 361; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection in people with DCM (data could not be pooled; studies = 7; participants = 361; very low-certainty evidence). We are uncertain whether SCT improves HRQoL (standardized mean difference (SMD) 0.62, 95% CI 0.01 to 1.23; I² = 72%; studies = 5, participants = 272; very low-certainty evidence) and functional capacity (6-minute walk test) (mean difference (MD) 70.12 m, 95% CI -5.28 to 145.51; I² = 87%; studies = 5, participants = 230; very low-certainty evidence). SCT may result in a slight functional class (New York Heart Association) improvement (data could not be pooled; studies = 6, participants = 398; low-certainty evidence). None of the included studies reported major adverse cardiovascular events as defined in our protocol. SCT may not increase the risk of ventricular arrhythmia (data could not be pooled; studies = 8, participants = 504; low-certainty evidence). When comparing SCT to cell mobilization with granulocyte-colony stimulating factor (G-CSF), we are uncertain whether SCT reduces all-cause mortality (RR 0.46, 95% CI 0.16 to 1.31; I² = 39%; studies = 3, participants = 195; very low-certainty evidence). We are uncertain whether SCT increases the risk of procedural complications associated with cells injection (studies = 1, participants = 60; very low-certainty evidence). SCT may not improve HRQoL (MD 4.61 points, 95% CI -5.62 to 14.83; studies = 1, participants = 22; low-certainty evidence). SCT may improve functional capacity (6-minute walk test) (MD 140.14 m, 95% CI 119.51 to 160.77; I² = 0%; studies = 2, participants = 155; low-certainty evidence). None of the included studies reported MACE as defined in our protocol or ventricular arrhythmia. The most commonly reported outcomes across studies were based on physiological measures of cardiac function where there were some beneficial effects suggesting potential benefits of SCT in people with non-ischaemic DCM. However, it is unclear if this intermediate effects translates into clinical benefits for these patients. With regard to specific aspects related to the modality of cell therapy and its delivery, uncertainties remain as subgroup analyses could not be performed as planned, making it necessary to wait for the publication of several studies that are currently in progress before any firm conclusion can be reached. AUTHORS' CONCLUSIONS We are uncertain whether SCT in people with DCM reduces the risk of all-cause mortality and procedural complications, improves HRQoL, and performance status (exercise capacity). SCT may improve functional class (NYHA), compared to usual care (no cells). Similarly, when compared to G-CSF, we are also uncertain whether SCT in people with DCM reduces the risk of all-cause mortality although some studies within this comparison observed a favourable effect that should be interpreted with caution. SCT may not improve HRQoL but may improve to some extent performance status (exercise capacity). Very low-quality evidence reflects uncertainty regarding procedural complications. These suggested beneficial effects of SCT, although uncertain due to the very low certainty of the evidence, are accompanied by favourable effects on some physiological measures of cardiac function. Presently, the most effective mode of administration of SCT and the population that could benefit the most is unclear. Therefore, it seems reasonable that use of SCT in people with DCM is limited to clinical research settings. Results of ongoing studies are likely to modify these conclusions.
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Affiliation(s)
- Rienzi Diaz-Navarro
- Department of Internal Medicine, School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
| | - Gerard Urrútia
- Iberoamerican Cochrane Centre, Biomedical Research Institute Sant Pau (IIB Sant Pau), CIBER Epidemiología y Salud Pública (CIBERESP), Barcelona, Spain
| | - John Gf Cleland
- National Heart and Lung Institute, Imperial College London, London, UK
| | - Daniel Poloni
- Department of Internal Medicine, School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
| | - Francisco Villagran
- Department of Internal Medicine, School of Medicine, Universidad de Valparaiso, Vina del Mar, Chile
| | - Roberto Acosta-Dighero
- Cochrane Chile Associate Centre, Universidad de Valparaíso, Valparaíso, Chile
- School of Physiotherapy, Faculty of Health Sciences, Universidad San Sebastian, Santiago, Chile
| | - Shrikant I Bangdiwala
- Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, Canada
| | - Gabriel Rada
- Department of Internal Medicine and Evidence-Based Healthcare Program, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
| | - Eva Madrid
- Interdisciplinary Centre for Health Studies CIESAL, Universidad de Valparaíso, Viña del Mar, Chile
- Cochrane Chile Associate Centre, Universidad de Valparaíso, Valparaíso, Chile
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14
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Mukherjee S, Yadav G, Kumar R. Recent trends in stem cell-based therapies and applications of artificial intelligence in regenerative medicine. World J Stem Cells 2021; 13:521-541. [PMID: 34249226 PMCID: PMC8246250 DOI: 10.4252/wjsc.v13.i6.521] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/16/2021] [Revised: 03/22/2021] [Accepted: 05/20/2021] [Indexed: 02/06/2023] Open
Abstract
Stem cells are undifferentiated cells that can self-renew and differentiate into diverse types of mature and functional cells while maintaining their original identity. This profound potential of stem cells has been thoroughly investigated for its significance in regenerative medicine and has laid the foundation for cell-based therapies. Regenerative medicine is rapidly progressing in healthcare with the prospect of repair and restoration of specific organs or tissue injuries or chronic disease conditions where the body’s regenerative process is not sufficient to heal. In this review, the recent advances in stem cell-based therapies in regenerative medicine are discussed, emphasizing mesenchymal stem cell-based therapies as these cells have been extensively studied for clinical use. Recent applications of artificial intelligence algorithms in stem cell-based therapies, their limitation, and future prospects are highlighted.
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Affiliation(s)
- Sayali Mukherjee
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Garima Yadav
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
| | - Rajnish Kumar
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow 226028, Uttar Pradesh, India
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15
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Mesenchymal stromal cell therapeutic potency is dependent upon viability, route of delivery, and immune match. Blood Adv 2021; 4:1987-1997. [PMID: 32384543 DOI: 10.1182/bloodadvances.2020001711] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2020] [Accepted: 04/12/2020] [Indexed: 12/11/2022] Open
Abstract
Culture-adapted bone marrow mesenchymal stromal cells (MSCs) deploy paracrine anti-inflammatory and tissue regenerative functionalities that can be harnessed as a living cell pharmaceutical product. Independent of clinical indication, a near majority of human clinical trials administer MSC IV, often with an allogeneic MSC cell product immediately after thawing from cryostorage. Despite hundreds of studies in a wide assortment of inflammatory, degenerative, and acute tissue injury syndromes, human clinical outcomes often fail to mirror promising rigorously conducted preclinical animal studies. Using a mouse model of toxic colitis, we demonstrate that replication fit MSCs harvested in log phase of growth have substantial impact on colitis clinical and pathologic endpoints when delivered subcutaneously or intraperitoneally, whereas the maximum tolerated IV bolus dosing failed to do so. We also demonstrate that heat-inactivated MSCs lose all therapeutic utility and the observation is mirrored by use of viable MSC administered immediately postthaw from cryostorage. Using luciferase transgenic MSC as donor cells, we demonstrate that transient in vivo engraftment is severely compromised when MSCs are dead or thawed and further demonstrate that MSC redosing is feasible in relapsing colitis, but only syngeneic MSCs lead to sustained improvement of clinical endpoints. These data support the notion that pharmaceutical potency of MSC requires viability and functional fitness. Reciprocally, IV administration of thawed MSC products may be biased against positive clinical outcomes for treatment of colitis and that extravascular administration of syngeneic, fit MSCs allows for effect in a recurrent therapy model.
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16
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Galipeau J, Krampera M, Leblanc K, Nolta JA, Phinney DG, Shi Y, Tarte K, Viswanathan S, Martin I. Mesenchymal stromal cell variables influencing clinical potency: the impact of viability, fitness, route of administration and host predisposition. Cytotherapy 2021; 23:368-372. [PMID: 33714704 PMCID: PMC11708105 DOI: 10.1016/j.jcyt.2020.11.007] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Revised: 10/14/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023]
Abstract
The International Society for Cell & Gene Therapy mesenchymal stromal cell (MSC) committee has been an interested observer of community interests in all matters related to MSC identity, mechanism of action, potency assessment and etymology, and it has regularly contributed to this conversation through a series of MSC pre-conferences and committee publications dealing with these matters. Arising from these reflections, the authors propose that an overlooked and potentially disruptive perspective is the impact of in vivo persistence on potency that is not predicted by surrogate cellular potency assays performed in vitro and how this translates to in vivo outcomes. Systemic delivery or extravascular implantation at sites removed from the affected organ system seems to be adequate in affecting clinical outcomes in many pre-clinical murine models of acute tissue injury and inflammatory pathology, including the recent European Medicines Agency-approved use of MSCs in Crohn-related fistular disease. The authors further propose that MSC viability and metabolic fitness likely dominate as a potency quality attribute, especially in recipients poised for salutary benefits as defined by emerging predictive biomarkers of response.
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Affiliation(s)
- Jacques Galipeau
- Department of Medicine, Carbone Cancer Center, University of Wisconsin, Madison, Wisconsin, USA.
| | - Mauro Krampera
- Department of Medicine, Section of Hematology, University of Verona, Verona, Italy
| | - Katarina Leblanc
- Department of Laboratory Medicine, Center for Allogeneic Stem Cell Transplantation, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden
| | - Jan A Nolta
- Stem Cell Program, University of California Davis, Sacramento, California, USA
| | - Donald G Phinney
- Department of Molecular Therapeutics, Scripps Research Institute, Jupiter, Florida, USA
| | - Yufang Shi
- Institute for Translational Medicine, Soochow University, Suzhou, China
| | - Karin Tarte
- Établissement Français du Sang Bretagne, Institute for Health and Medical Research, University of Rennes, Rennes, France
| | - Sowmya Viswanathan
- Department of Medicine and Institute of Biomedical Engineering, Krembil Research Institute, University Health Network, University of Toronto, Toronto, Canada
| | - Ivan Martin
- Department of Biomedicine, University Hospital Basel, Basel, Switzerland
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17
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Bartunek J, Terzic A, Davison BA, Behfar A, Sanz‐Ruiz R, Wojakowski W, Sherman W, Heyndrickx GR, Metra M, Filippatos GS, Waldman SA, Teerlink JR, Henry TD, Gersh BJ, Hajjar R, Tendera M, Senger S, Cotter G, Povsic TJ, Wijns W. Cardiopoietic stem cell therapy in ischaemic heart failure: long-term clinical outcomes. ESC Heart Fail 2020; 7:3345-3354. [PMID: 33094909 PMCID: PMC7754898 DOI: 10.1002/ehf2.13031] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/03/2020] [Revised: 09/01/2020] [Accepted: 09/09/2020] [Indexed: 12/16/2022] Open
Abstract
AIMS This study aims to explore long-term clinical outcomes of cardiopoiesis-guided stem cell therapy for ischaemic heart failure assessed in the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial. METHODS AND RESULTS CHART-1 is a multinational, randomized, and double-blind trial conducted in 39 centres in heart failure patients (n = 315) on standard-of-care therapy. The 'active' group received cardiopoietic stem cells delivered intramyocardially using a retention-enhanced catheter. The 'control' group underwent patient-level sham procedure. Patients were followed up to 104 weeks. In the entire study population, results of the primary hierarchical composite outcome were maintained neutral at Week 52 [Mann-Whitney estimator 0.52, 95% confidence interval (CI) 0.45-0.59, P = 0.51]. Landmark analyses suggested late clinical benefit in patients with significant left ventricular enlargement receiving adequate dosing. Specifically, beyond 100 days of follow-up, patients with left ventricular end-diastolic volume of 200-370 mL treated with ≤19 injections of cardiopoietic stem cells showed reduced risk of death or cardiovascular hospitalization (hazard ratio 0.38, 95% CI 0.16-0.91, P = 0.031) and cardiovascular death or heart failure hospitalization (hazard ratio 0.28, 95% CI 0.09-0.94, P = 0.040). Cardiopoietic stem cell therapy was well tolerated long term with no difference in safety readouts compared with sham at 2 years. CONCLUSIONS Longitudinal follow-up documents that cardiopoietic stem cell therapy is overall safe, and post hoc analyses suggest benefit in an ischaemic heart failure subpopulation defined by advanced left ventricular enlargement on tolerable stem cell dosing. The long-term clinical follow-up thus offers guidance for future targeted trials.
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Affiliation(s)
- Jozef Bartunek
- Cardiovascular CenterOLV HospitalMoorselbaan 164AalstB‐9300Belgium
| | - Andre Terzic
- Cardiovascular CenterOLV HospitalMoorselbaan 164AalstB‐9300Belgium
- Department of Cardiovascular MedicineMayo Clinic, Center for Regenerative Medicine200 First Street SWRochesterMN55905USA
| | | | - Atta Behfar
- Department of Cardiovascular MedicineMayo Clinic, Center for Regenerative Medicine200 First Street SWRochesterMN55905USA
| | - Ricardo Sanz‐Ruiz
- Cardiology DepartmentHospital General Universitario Gregorio Marañón and CIBERCV (Instituto de Salud Carlos III)MadridSpain
| | - Wojciech Wojakowski
- Department of Cardiology and Structural Heart DiseaseMedical University of SilesiaKatowicePoland
| | | | | | - Marco Metra
- Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public HealthUniversity and Spedali CiviliBresciaItaly
| | - Gerasimos S. Filippatos
- National and Kapodistrian University of Athens, School of MedicineAttikon University HospitalAthensGreece
| | - Scott A. Waldman
- Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaPAUSA
| | - John R. Teerlink
- School of MedicineUniversity of California San FranciscoSan FranciscoCAUSA
- Section of CardiologySan Francisco Veterans Affairs Medical CenterSan FranciscoCAUSA
| | - Timothy D. Henry
- The Carl Edyth Lindner Center for Research and Education at The Christ HospitalCincinnatiOHUSA
| | - Bernard J. Gersh
- Department of Cardiovascular MedicineMayo Clinic, Center for Regenerative Medicine200 First Street SWRochesterMN55905USA
| | | | - Michal Tendera
- Department of Cardiology and Structural Heart DiseaseMedical University of SilesiaKatowicePoland
| | | | | | - Thomas J. Povsic
- Duke Clinical Research Institute and Duke University Medical CenterDurhamNCUSA
| | - William Wijns
- The Lambe Institute for Translational Medicine and CuramNational University of Ireland Galway and Saolta University Healthcare GroupGalwayIreland
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18
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Jackson AO, Rahman GA, Yin K, Long S. Enhancing Matured Stem-Cardiac Cell Generation and Transplantation: A Novel Strategy for Heart Failure Therapy. J Cardiovasc Transl Res 2020; 14:556-572. [PMID: 33258081 DOI: 10.1007/s12265-020-10085-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2020] [Accepted: 11/10/2020] [Indexed: 12/25/2022]
Abstract
Heart failure (HF) remains one of the major causes of morbidity and mortality worldwide. Recent studies have shown that stem cells (SCs) including bone marrow mesenchymal stem (BMSC), embryonic bodies (EB), embryonic stem (ESC), human induced pluripotent stem (hiPSC)-derived cardiac cells generation, and transplantation treated myocardial infarction (MI) in vivo and in human. However, the immature phenotypes compromise their clinical application requiring immediate intervention to improve stem-derived cardiac cell (S-CCs) maturation. Recently, an unbiased multi-omic analysis involving genomics, transcriptomics, epigenomics, proteomics, and metabolomics identified specific strategies for the generation of matured S-CCs that may enhance patients' recovery processes upon transplantation. However, these strategies still remain undisclosed. Here, we summarize the recently discovered strategies for the matured S-CC generation. In addition, cardiac patch formation and transplantation that accelerated HF recuperation in clinical trials are discussed. A better understanding of this work may lead to efficient generation of matured S-CCs for regenerative medicine. Graphical abstract.
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Affiliation(s)
- Ampadu O Jackson
- Department of Biochemistry and Molecular Biology, University of South China, Hengyang, 421001, Hunan Province, China.,International College, University of South China, Hengyang, 421001, Hunan Province, China.,Cape Coast Teaching Hospital, Cape Coast, Department of Surgery, School of Medical Science, University of Cape Coast, Cape Coast, Ghana
| | - Ganiyu A Rahman
- Cape Coast Teaching Hospital, Cape Coast, Department of Surgery, School of Medical Science, University of Cape Coast, Cape Coast, Ghana
| | - Kai Yin
- The Second Affiliated Hospital of Guilin Medical University, Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University, Guilin, China
| | - Shiyin Long
- Department of Biochemistry and Molecular Biology, University of South China, Hengyang, 421001, Hunan Province, China.
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19
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Li M, Yamada S, Shi A, Singh RD, Rolland TJ, Jeon R, Lopez N, Shelerud L, Terzic A, Behfar A. Brachyury engineers cardiac repair competent stem cells. Stem Cells Transl Med 2020; 10:385-397. [PMID: 33098750 PMCID: PMC7900595 DOI: 10.1002/sctm.20-0193] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Revised: 08/06/2020] [Accepted: 08/24/2020] [Indexed: 12/11/2022] Open
Abstract
To optimize the regenerative proficiency of stem cells, a cardiopoietic protein-based cocktail consisting of multiple growth factors has been developed and advanced into clinical trials for treatment of ischemic heart failure. Streamlining the inductors of cardiopoiesis would address the resource intensive nature of the current stem cell enhancement protocol. To this end, the microencapsulated-modified-mRNA (M3 RNA) technique was here applied to introduce early cardiogenic genes into human adipose-derived mesenchymal stem cells (AMSCs). A single mesodermal transcription factor, Brachyury, was sufficient to trigger high expression of cardiopoietic markers, Nkx2.5 and Mef2c. Engineered cardiopoietic stem cells (eCP) featured a transcriptome profile distinct from pre-engineered AMSCs. In vitro, eCP demonstrated protective antioxidant capacity with enhanced superoxide dismutase expression and activity; a vasculogenic secretome driving angiogenic tube formation; and macrophage polarizing immunomodulatory properties. In vivo, in a murine model of myocardial infarction, intramyocardial delivery of eCP (600 000 cells per heart) improved cardiac performance and protected against decompensated heart failure. Thus, heart repair competent stem cells, armed with antioxidant, vasculogenic, and immunomodulatory traits, are here engineered through a protein-independent single gene manipulation, expanding the available regenerative toolkit.
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Affiliation(s)
- Mark Li
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA
| | - Satsuki Yamada
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Division of Geriatric Medicine and Gerontology, Department of Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ao Shi
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota, USA
| | - Raman Deep Singh
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Tyler J Rolland
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Ryounghoon Jeon
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Natalia Lopez
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Lukas Shelerud
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA
| | - Andre Terzic
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.,Department of Clinical Genomics, Mayo Clinic, Rochester, Minnesota, USA
| | - Atta Behfar
- Center for Regenerative Medicine, Van Cleve Cardiac Regenerative Medicine Program, Marriott Heart Disease Research Program, Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota, USA.,Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota, USA.,Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, Minnesota, USA
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20
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Li C, Naveed M, Dar K, Liu Z, Baig MMFA, Lv R, Saeed M, Dingding C, Feng Y, Xiaohui Z. Therapeutic advances in cardiac targeted drug delivery: from theory to practice. J Drug Target 2020; 29:235-248. [PMID: 32933319 DOI: 10.1080/1061186x.2020.1818761] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The most commonly used administration methods in clinics and life are oral administration, intravenous injection, and other systemic administration methods. Targeted administration must be an essential long-term development direction due to the limited availability and a high incidence of systemic side effects. Cardiovascular diseases (CVD) are the leading cause of death all over the world. Targeted drug delivery (TDD) methods with the heart as the target organ have developed rapidly and are diversified. This article reviews the research progress of various TDD methods around the world with a heart as the target organ. It is mainly divided into two parts: the targeting vector represented by nanoparticles and various TDD methods such as intracoronary injection, ventricular wall injection, pericardial injection, and implantable medical device therapy and put forward some suggestions on the development of targeting. Different TDD methods described in this paper have not been widely used in clinical practice, and some have not even completed preclinical studies. Targeted drug delivery still requires long-term efforts by many researchers to realize the true meaning of the heart. HIGHLIGHTS Targeted administration can achieve a better therapeutic effect and effectively reduce the occurrence of adverse reactions. Parenteral administration or medical device implantation can be used for targeted drug delivery. Combined with new dosage forms or new technologies, better-targeted therapy can be achieved. Clinical trials have confirmed the safety and effectiveness of several administration methods.
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Affiliation(s)
- Cuican Li
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Muhammad Naveed
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China.,School of Pharmacy, Nanjing Medical University, Nanjing, P. R. China
| | - Kashif Dar
- Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Medical University, Nanjing, P. R. China
| | - Ziwei Liu
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Mirza Muhammad Faran Ashraf Baig
- State Key Laboratory of Analytical Chemistry for Life Sciences, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, P. R. China
| | - Rundong Lv
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Muhammad Saeed
- Faculty of Animal Production and Technology, The Cholistan University of Veterinary and Animal Sciences, Bahawalpur, Pakistan
| | - Chen Dingding
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Yu Feng
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China
| | - Zhou Xiaohui
- Department of Clinical Pharmacy, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, P. R. China.,Department of Heart Surgery, Nanjing Shuiximen Hospital, Nanjing, P. R. China.,Department of Cardiothoracic Surgery, Zhongda Hospital affiliated with Southeast University, Nanjing, P. R. China
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21
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Abstract
Mesenchymal stem cells (MSCs), also referred to as multipotent stromal cells or mesenchymal stromal cells, are present in multiple tissues and capable of differentiating into diverse cell lineages, holding a great promise in developing cell-based therapy for a wide range of conditions. Pelvic floor disorders (PFDs) is a common degenerative disease in women and may diminish a woman's quality of life at any age. Since the treatments for this disease are limited by the high rates of recurrence and surgical complications, seeking an ideal therapy in the restoration of pelvic floor function is an urgent issue at present. Herein, we summarize the cell sources of MSCs used for PFDs and discuss the potential mechanisms of MSCs in treating PFDs. Specifically, we also provide a comprehensive review of current preclinical and clinical trials dedicated to investigating MSC-based therapy for PFDs. The novel therapy has presented promising therapeutic effects which include relieving the symptoms of urinary or fecal incontinence, improving the biological properties of implanted meshes and promoting the injured tissue repair. Nevertheless, MSC-based therapies for PFDs are still experimental and the unstated issues on their safety and efficacy should be carefully addressed before their clinical applications.
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22
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Wu X, Jiang J, Gu Z, Zhang J, Chen Y, Liu X. Mesenchymal stromal cell therapies: immunomodulatory properties and clinical progress. Stem Cell Res Ther 2020; 11:345. [PMID: 32771052 PMCID: PMC7414268 DOI: 10.1186/s13287-020-01855-9] [Citation(s) in RCA: 166] [Impact Index Per Article: 33.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2020] [Revised: 07/09/2020] [Accepted: 07/27/2020] [Indexed: 02/08/2023] Open
Abstract
Mesenchymal stromal cells (MSCs) are a subset of heterogeneous non-hematopoietic fibroblast-like cells that can differentiate into cells of multiple lineages, such as chondrocytes, osteoblasts, adipocytes, myoblasts, and others. These multipotent MSCs can be found in nearly all tissues but mostly located in perivascular niches, playing a significant role in tissue repair and regeneration. Additionally, MSCs interact with immune cells both in innate and adaptive immune systems, modulating immune responses and enabling immunosuppression and tolerance induction. Understanding the biology of MSCs and their roles in clinical treatment is crucial for developing MSC-based cellular therapy for a variety of pathological conditions. Here, we review the progress in the study on the mechanisms underlying the immunomodulatory and regenerative effects of MSCs; update the medical translation of MSCs, focusing on the registration trials leading to regulatory approvals; and discuss how to improve therapeutic efficacy and safety of MSC applications for future.
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Affiliation(s)
- Xiaomo Wu
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China.,Department of Biomedicine, University of Basel, Klingelbergstr 70, CH-4056, Basel, Switzerland
| | - Ju Jiang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Zhongkai Gu
- The Institute of Biomedical Sciences, Fudan University, Mingdao Building, Dongan Road 131, Shanghai, 200032, China
| | - Jinyan Zhang
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China
| | - Yang Chen
- Dermatology Institute of Fuzhou, Dermatology Hospital of Fuzhou, Xihong Road 243, Fuzhou, 350025, China.
| | - Xiaolong Liu
- The United Innovation of Mengchao Hepatobiliary Technology Key Laboratory of Fujian Province, Mengchao Hepatobiliary Hospital of Fujian Medical University, Xihong Road 312, Fuzhou, 350025, China.
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23
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Zheng G, Xie ZY, Wang P, Wu YF, Shen HY. Recent advances of single-cell RNA sequencing technology in mesenchymal stem cell research. World J Stem Cells 2020; 12:438-447. [PMID: 32742561 PMCID: PMC7360991 DOI: 10.4252/wjsc.v12.i6.438] [Citation(s) in RCA: 10] [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: 02/29/2020] [Revised: 05/13/2020] [Accepted: 05/27/2020] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cells (MSCs) are multipotent stromal cells with great potential for clinical applications. However, little is known about their cell heterogeneity at a single-cell resolution, which severely impedes the development of MSC therapy. In this review, we focus on advances in the identification of novel surface markers and functional subpopulations of MSCs made by single-cell RNA sequencing and discuss their participation in the pathophysiology of stem cells and related diseases. The challenges and future directions of single-cell RNA sequencing in MSCs are also addressed in this review.
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Affiliation(s)
- Guan Zheng
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Zhong-Yu Xie
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Peng Wang
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
| | - Yan-Feng Wu
- Center for Biotherapy, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, Guangdong Province, China
| | - Hui-Yong Shen
- Department of Orthopedics, The Eighth Affiliated Hospital, Sun Yat-sen University, Shenzhen 518033, Guangdong Province, China
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24
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Turner D, Rieger AC, Balkan W, Hare JM. Clinical-based Cell Therapies for Heart Disease-Current and Future State. Rambam Maimonides Med J 2020; 11:RMMJ.10401. [PMID: 32374254 PMCID: PMC7202446 DOI: 10.5041/rmmj.10401] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Patients have an ongoing unmet need for effective therapies that reverse the cellular and functional damage associated with heart damage and disease. The discovery that ~1%-2% of adult cardiomyocytes turn over per year provided the impetus for treatments that stimulate endogenous repair mechanisms that augment this rate. Preclinical and clinical studies provide evidence that cell-based therapy meets these therapeutic criteria. Recent and ongoing studies are focused on determining which cell type(s) works best for specific patient population(s) and the mechanism(s) by which these cells promote repair. Here we review clinical and preclinical stem cell studies and anticipate future directions of regenerative medicine for heart disease.
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Affiliation(s)
- Darren Turner
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Angela C. Rieger
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- To whom correspondence should be addressed. E-mail:
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25
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Arrell DK, Rosenow CS, Yamada S, Behfar A, Terzic A. Cardiopoietic stem cell therapy restores infarction-altered cardiac proteome. NPJ Regen Med 2020; 5:5. [PMID: 32194990 PMCID: PMC7067830 DOI: 10.1038/s41536-020-0091-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2019] [Accepted: 02/14/2020] [Indexed: 12/20/2022] Open
Abstract
Cardiopoietic stem cells have reached advanced clinical testing for ischemic heart failure. To profile their molecular influence on recipient hearts, systems proteomics was here applied in a chronic model of infarction randomized with and without human cardiopoietic stem cell treatment. Multidimensional label-free tandem mass spectrometry resolved and quantified 3987 proteins constituting the cardiac proteome. Infarction altered 450 proteins, reduced to 283 by stem cell treatment. Notably, cell therapy non-stochastically reversed a majority of infarction-provoked changes, remediating 85% of disease-affected protein clusters. Pathway and network analysis decoded functional reorganization, distinguished by prioritization of vasculogenesis, cardiac development, organ regeneration, and differentiation. Subproteome restoration nullified adverse ischemic effects, validated by echo-/electro-cardiographic documentation of improved cardiac chamber size, reduced QT prolongation and augmented ejection fraction post-cell therapy. Collectively, cardiopoietic stem cell intervention transitioned infarcted hearts from a cardiomyopathic trajectory towards pre-disease. Systems proteomics thus offers utility to delineate and interpret complex molecular regenerative outcomes.
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Affiliation(s)
- D. Kent Arrell
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN USA
- Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN USA
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN USA
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN USA
| | - Christian S. Rosenow
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN USA
- Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN USA
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN USA
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA
| | - Satsuki Yamada
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN USA
- Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN USA
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN USA
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA
- Division of Geriatric Medicine & Gerontology, Department of Medicine, Mayo Clinic, Rochester, MN USA
| | - Atta Behfar
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN USA
- Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN USA
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN USA
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN USA
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN USA
| | - Andre Terzic
- Center for Regenerative Medicine, Mayo Clinic, Rochester, MN USA
- Marriott Heart Disease Research Program, Mayo Clinic, Rochester, MN USA
- Van Cleve Cardiac Regenerative Medicine Program, Mayo Clinic, Rochester, MN USA
- Department of Cardiovascular Medicine, Mayo Clinic, Rochester, MN USA
- Department of Molecular Pharmacology & Experimental Therapeutics, Mayo Clinic, Rochester, MN USA
- Department of Medical Genetics, Mayo Clinic, Rochester, MN USA
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26
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Gomez-Salazar M, Gonzalez-Galofre ZN, Casamitjana J, Crisan M, James AW, Péault B. Five Decades Later, Are Mesenchymal Stem Cells Still Relevant? Front Bioeng Biotechnol 2020; 8:148. [PMID: 32185170 PMCID: PMC7058632 DOI: 10.3389/fbioe.2020.00148] [Citation(s) in RCA: 97] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2019] [Accepted: 02/13/2020] [Indexed: 12/13/2022] Open
Abstract
Mesenchymal stem cells are culture-derived mesodermal progenitors isolatable from all vascularized tissues. In spite of multiple fundamental, pre-clinical and clinical studies, the native identity and role in tissue repair of MSCs have long remained elusive, with MSC selection in vitro from total cell suspensions essentially unchanged as a mere primary culture for half a century. Recent investigations have helped understand the tissue origin of these progenitor cells, and uncover alternative effects of MSCs on tissue healing via growth factor secretion and interaction with the immune system. In this review, we describe current trends in MSC biology and discuss how these may improve the use of these therapeutic cells in tissue engineering and regenerative medicine.
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Affiliation(s)
- Mario Gomez-Salazar
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Zaniah N Gonzalez-Galofre
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Joan Casamitjana
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Mihaela Crisan
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom
| | - Aaron W James
- Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States.,Department of Pathology, Johns Hopkins University, Baltimore, MD, United States
| | - Bruno Péault
- MRC Centre for Regenerative Medicine and Centre for Cardiovascular Science, The University of Edinburgh, Edinburgh, United Kingdom.,Orthopaedic Hospital Research Center and Broad Stem Cell Research Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, United States
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27
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Galland S, Stamenkovic I. Mesenchymal stromal cells in cancer: a review of their immunomodulatory functions and dual effects on tumor progression. J Pathol 2019; 250:555-572. [PMID: 31608444 PMCID: PMC7217065 DOI: 10.1002/path.5357] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/03/2019] [Accepted: 10/04/2019] [Indexed: 12/12/2022]
Abstract
Mesenchymal stem or stromal cells (MSCs) are pluripotent cells implicated in a broad range of physiological events, including organogenesis and maintenance of tissue homeostasis as well as tissue regeneration and repair. Because their current definition is somewhat loose – based primarily on their ability to differentiate into a variety of mesenchymal tissues, adhere to plastic, and express, or lack, a handful of cell surface markers – MSCs likely encompass several subpopulations, which may have diverse properties. Their diversity may explain, at least in part, the pleiotropic functions that they display in different physiological and pathological settings. In the context of tissue injury, MSCs can respectively promote and attenuate inflammation during the early and late phases of tissue repair. They may thereby act as sensors of the inflammatory response and secrete mediators that boost or temper the response as required by the stage of the reparatory and regenerative process. MSCs are also implicated in regulating tumor development, in which they are increasingly recognized to play a complex role. Thus, MSCs can both promote and constrain tumor progression by directly affecting tumor cells via secreted mediators and cell–cell interactions and by modulating the innate and adaptive immune response. This review summarizes our current understanding of MSC involvement in tumor development and highlights the mechanistic underpinnings of their implication in tumor growth and progression. © 2020 Authors. Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Sabine Galland
- Laboratory of Experimental Pathology, Institute of Pathology, CHUV, Lausanne, Switzerland
| | - Ivan Stamenkovic
- Laboratory of Experimental Pathology, Institute of Pathology, CHUV, Lausanne, Switzerland
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28
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Tehzeeb J, Manzoor A, Ahmed MM. Is Stem Cell Therapy an Answer to Heart Failure: A Literature Search. Cureus 2019; 11:e5959. [PMID: 31803548 PMCID: PMC6874291 DOI: 10.7759/cureus.5959] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The heart is one of the most industrious organs in the human body. It starts beating in the first few weeks of embryonic life and keeps pumping blood till death. This organ can host a range of diseases as well. Some can hamper the vasculature, while others can affect its electrical activity, the heart valves, etc. All these conditions can lead to end-stage failure where it can no longer meet the requirements of the body’s milieu. This imbalance between supply and demand leads to an array of symptoms. Medical management can reduce these clinical effects and possibly prolong the life expectancy in such patients. However, prescription medications can also have their own adverse effects. This necessitates that each line of treatment should be assessed on a risk vs benefit basis. The conventional approach has been to try and slow down the progression of heart failure (HF). However, the inception of stem cells in the management of HF has the potential for reversal of this pathology. Keeping this in view, many studies and trials are under process. To turn the clock back on the HF, before complications set in or get out of control, is the main focus of the time. This article attempts to evaluate various studies about stem cell therapy (SCT) and highlight the important aspects of this novel modality in changing patients' lives.
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Affiliation(s)
- Javaria Tehzeeb
- Internal Medicine, Mayo Hospital, King Edward Medical University, Lahore, PAK
| | - Anam Manzoor
- Internal Medicine, Mayo Hospital, King Edward Medical University, Lahore, PAK
| | - Munis M Ahmed
- Internal Medicine, St Mary Mercy Livonia Hospital, Livonia, USA
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29
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Lv K, Li Q, Zhang L, Wang Y, Zhong Z, Zhao J, Lin X, Wang J, Zhu K, Xiao C, Ke C, Zhong S, Wu X, Chen J, Yu H, Zhu W, Li X, Wang B, Tang R, Wang J, Huang J, Hu X. Incorporation of small extracellular vesicles in sodium alginate hydrogel as a novel therapeutic strategy for myocardial infarction. Am J Cancer Res 2019; 9:7403-7416. [PMID: 31695776 PMCID: PMC6831299 DOI: 10.7150/thno.32637] [Citation(s) in RCA: 156] [Impact Index Per Article: 26.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2019] [Accepted: 08/15/2019] [Indexed: 12/26/2022] Open
Abstract
Bone marrow mesenchymal stem cell (MSC)-derived small extracellular vesicles (sEVs) have been widely used for treating myocardial infarction (MI). However, low retention and short-lived therapeutic effects are still significant challenges. This study aimed to determine whether incorporation of MSC-derived sEVs in alginate hydrogel increases their retention in the heart thereby improving therapeutic effects. Methods: The optimal sodium alginate hydrogel incorporating sEVs system was determined by its release ability of sEVs and rheology of hydrogel. Ex vivo fluorescence imaging was utilized to evaluate the retention of sEVs in the heart. Immunoregulation and effects of sEVs on angiogenesis were analyzed by immunofluorescence staining. Echocardiography and Masson's trichrome staining were used to estimate cardiac function and infarct size. Results: The delivery of sEVs incorporated in alginate hydrogel (sEVs-Gel) enhanced their retention in the heart. Compared with sEVs only treatment (sEVs), sEVs-Gel treatment significantly decreased cardiac cell apoptosis and promoted the polarization of macrophages at day 3 after MI. sEVs-Gel treatment also increased scar thickness and angiogenesis at four weeks post-infarction. Measurement of cardiac function and infarct size were significantly better in the sEVs-Gel group than in the group treated with sEVs only. Conclusion: Delivery of sEVs incorporated in alginate hydrogel provides a novel approach of cell-free therapy and optimizes the therapeutic effect of sEVs for MI.
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30
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Sciatti E, Dallapellegrina L, Metra M, Lombardi CM. New drugs for the treatment of chronic heart failure with a reduced ejection fraction. J Cardiovasc Med (Hagerstown) 2019; 20:650-659. [DOI: 10.2459/jcm.0000000000000850] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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31
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Jayaraj JS, Janapala RN, Qaseem A, Usman N, Fathima N, Kashif T, Reddy VK, Bakshi S. Efficacy and Safety of Stem Cell Therapy in Advanced Heart Failure Patients: A Systematic Review with a Meta-analysis of Recent Trials Between 2017 and 2019. Cureus 2019; 11:e5585. [PMID: 31696004 PMCID: PMC6820892 DOI: 10.7759/cureus.5585] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Objective The effects of stem cell therapy in patients with advanced heart failure is an ongoing debate. This study aimed to assess the effectiveness and safety of stem cell therapy plus the standard of care as compared to the placebo plus the standard of care in advanced heart failure patients. Methods A comprehensive keyword search of PubMed between 2017 and 2019 was performed to extract trials conducted with stem cell therapy controlled with placebo in advanced heart failure. We included randomized controlled trials (RCTs) with data on safety and efficacy in patients with advanced heart failure after stem cell transplantation. Results Six RCTs, consisting of 569 patients, were selected. Three-hundred sixty-seven (367) out of 369 participants from the eligible four out of six RCTs were included for efficacy analysis, as we lost two patients from the final analysis due to early death. Five-hundred twenty-six (526) out of 527 participants from the eligible five out of six RCTs were included for safety analysis, as we lost one patient from the final analysis for not being able to receive the intervention. Stem cell transplantation significantly improved left ventricular ejection fraction (LVEF) by 4.58% (95% CI: 3.73-5.43%; p = 0.00001), improved left ventricular end-systolic volume (LVESV) by -5.18 ml (95% CI: -9.74 to -0.63 ml; p =0.03), and there was no difference in the risk of all-cause mortality (OR 0.97; 95% CI: 0.52 to 1.78%; p = 0.91). The above results correlate with the previous meta-analysis data conducted in 2016. Conclusions This meta-analysis provided the cumulative efficacy and safety results of stem cell transplantation in advanced heart failure based on recent RCTs. The above results suggest that stem cell therapy was associated with a moderate improvement in LVEF, and the safety analysis indicates no increased risk of mortality in patients with advanced heart failure. This meta-analysis recommends conducting more RCTs comparing stem cell transplantation and placebo with a larger patient population and longer follow-up.
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Affiliation(s)
- Joseph S Jayaraj
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Rajesh Naidu Janapala
- Internal Medicine, Icahn School of Medicine at Mount Sinai, Queens Hospital Center, New York, USA
| | - Aisha Qaseem
- Internal Medicine, Emory Johns Creek Hospital, Georgia, USA
| | - Norina Usman
- Internal Medicine, Veterans Affairs Palo Alto Health Care System - Stanford University School of Medicine, Palo Alto, USA
| | - Nida Fathima
- Internal Medicine, Sri Siddhartha Medical College, Tumkur, IND
| | - Tooba Kashif
- Cardiology, Heart and Vascular Institute, Dearborn, USA
| | - Vineeth K Reddy
- Internal Medicine, Sri Ramachandra Institute of Higher Education and Research, Chennai, IND
| | - Sanjiv Bakshi
- Cardiology, Icahn School of Medicine at Mount Sinai , Queens Hospital Center, New York, USA
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32
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Janssens SP. Mesenchymal Cell Therapy for Dilated Cardiomyopathy: Time to Test the Water. J Am Coll Cardiol 2019; 69:538-540. [PMID: 28153109 DOI: 10.1016/j.jacc.2016.11.044] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/22/2016] [Accepted: 11/28/2016] [Indexed: 11/17/2022]
Affiliation(s)
- Stefan P Janssens
- Department of Cardiovascular Diseases, University Hospital Leuven, Leuven, Belgium.
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33
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Landin AM, Hare JM. The quest for a successful cell-based therapeutic approach for heart failure. Eur Heart J 2018; 38:661-664. [PMID: 28073861 DOI: 10.1093/eurheartj/ehw626] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Affiliation(s)
- Ana Marie Landin
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, FL, USA.,Department of Medicine, University of Miami Miller School of Medicine, Miami, FL, USA
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34
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Fu H, Chen Q. Mesenchymal stem cell therapy for heart failure: a meta-analysis. Herz 2018; 45:557-563. [PMID: 30341444 DOI: 10.1007/s00059-018-4762-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2018] [Revised: 07/30/2018] [Accepted: 09/13/2018] [Indexed: 12/14/2022]
Abstract
BACKGROUND Mesenchymal stem cell (MSC) treatment has emerged as an important adjunct therapy for heart failure. However, the use of MSC to treat heart failure has not been well established. We conducted a systematic review and meta-analysis to evaluate the efficacy of MSC treatment for heart failure. METHODS PubMed, Embase, and the Cochrane Central Register of Controlled Trials were searched. Randomized controlled trials (RCTs) assessing the influence of MSC treatment on cardiac function in heart failure were included in this analysis. Two investigators independently searched the articles, extracted data, and assessed the quality of the included studies. Meta-analysis was performed using the fixed-effect model or random-effect model when appropriate. RESULTS Six RCTs involving 625 patients were included in the meta-analysis. Compared with control interventions in heart failure patients, MSC treatment had no significant influence on cardiovascular death (RR = 0.76; 95% CI = 0.38-1.52; p = 0.43); however, it was associated with significantly increased left ventricular ejection fraction (LVEF; mean = 9.64; 95% CI = 7.56-11.71; p < 0.00001) and reduced rehospitalization rate (RR = 0.41; 95% CI = 0.23-0.73; p = 0.003). In addition, no significant difference between the two groups was observed for the incidence of myocardial infarction (RR = 0.72; 95% CI = 0.10-5.02; p = 0.74), the recurrence of heart failure (RR = 0.88; 95% CI = 0.28-2.81; p = 0.83), and total death (RR = 0.68; 95% CI = 0.37-1.25; p = 0.21). CONCLUSION Although MSC treatment can significantly improve LVEF and reduce rehospitalization rates, it does not have a significant influence on cardiovascular death, myocardial infarction, heart failure, and total death.
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Affiliation(s)
- H Fu
- Department of Cardiology, Medical School, Jiangjin Central Hospital of Chongqing, No. 725 Jiangzhou Road Jiangjin district, 402260, Chongqing, China
| | - Q Chen
- Department of Cardiology, Medical School, Jiangjin Central Hospital of Chongqing, No. 725 Jiangzhou Road Jiangjin district, 402260, Chongqing, China.
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35
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Singh RD, Hillestad ML, Livia C, Li M, Alekseev AE, Witt TA, Stalboerger PG, Yamada S, Terzic A, Behfar A. M 3RNA Drives Targeted Gene Delivery in Acute Myocardial Infarction. Tissue Eng Part A 2018; 25:145-158. [PMID: 30047313 DOI: 10.1089/ten.tea.2017.0445] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
IMPACT STATEMENT The M3RNA (microencapsulated modified messenger RNA) platform is an approach to deliver messenger RNA (mRNA) in vivo, achieving a nonintegrating and viral-free approach to gene therapy. This technology was, in this study, tested for its utility in the myocardium, providing a unique avenue for targeted gene delivery into the freshly infarcted myocardial tissue. This study provides the evidentiary basis for the use of M3RNA in the heart through depiction of its performance in cultured cells, healthy rodent myocardium, and acutely injured porcine hearts. By testing the technology in large animal models of infarction, compatibility of M3RNA with current coronary intervention procedures was verified.
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Affiliation(s)
- Raman Deep Singh
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Matthew L Hillestad
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Christopher Livia
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota.,3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Mark Li
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota.,3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Alexey E Alekseev
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota.,4 Institute of Theoretical and Experimental Biophysics, Russian Academy of Science, Moscow, Russia
| | - Tyra A Witt
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Paul G Stalboerger
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Satsuki Yamada
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota
| | - Andre Terzic
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota.,3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
| | - Atta Behfar
- 1 Department of Cardiovascular Medicine, Mayo Clinic, Rochester, Minnesota.,2 VanCleve Cardiac Regenerative Medicine Program, Center for Regenerative Medicine, Mayo Clinic, Rochester, Minnesota.,3 Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, Minnesota
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Cellular self-assembly into 3D microtissues enhances the angiogenic activity and functional neovascularization capacity of human cardiopoietic stem cells. Angiogenesis 2018; 22:37-52. [PMID: 30014173 DOI: 10.1007/s10456-018-9635-4] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Accepted: 07/03/2018] [Indexed: 12/24/2022]
Abstract
While cell therapy has been proposed as next-generation therapy to treat the diseased heart, current strategies display only limited clinical efficacy. Besides the ongoing quest for the ideal cell type, in particular the very low retention rate of single-cell (SC) suspensions after delivery remains a major problem. To improve cellular retention, cellular self-assembly into 3D microtissues (MTs) prior to transplantation has emerged as an encouraging alternative. Importantly, 3D-MTs have also been reported to enhance the angiogenic activity and neovascularization potential of stem cells. Therefore, here using the chorioallantoic membrane (CAM) assay we comprehensively evaluate the impact of cell format (SCs versus 3D-MTs) on the angiogenic potential of human cardiopoietic stem cells, a promising second-generation cell type for cardiac repair. Biodegradable collagen scaffolds were seeded with human cardiopoietic stem cells, either as SCs or as 3D-MTs generated by using a modified hanging drop method. Thereafter, seeded scaffolds were placed on the CAM of living chicken embryos and analyzed for their perfusion capacity in vivo using magnetic resonance imaging assessment which was then linked to a longitudinal histomorphometric ex vivo analysis comprising blood vessel density and characteristics such as shape and size. Cellular self-assembly into 3D-MTs led to a significant increase of vessel density mainly driven by a higher number of neo-capillary formation. In contrast, SC-seeded scaffolds displayed a higher frequency of larger neo-vessels resulting in an overall 1.76-fold higher total vessel area (TVA). Importantly, despite that larger TVA in SC-seeded group, the mean perfusion capacity (MPC) was comparable between groups, therefore suggesting functional superiority together with an enhanced perfusion efficacy of the neo-vessels in 3D-MT-seeded scaffolds. This was further underlined by a 1.64-fold higher perfusion ratio when relating MPC to TVA. Our study shows that cellular self-assembly of human cardiopoietic stem cells into 3D-MTs substantially enhances their overall angiogenic potential and their functional neovascularization capacity. Hence, the concept of 3D-MTs may be considered to increase the therapeutic efficacy of future cell therapy concepts.
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Abstract
The idiom heart of the matter refers to the focal point within a topic and, with regard to health and longevity, the heart is truly pivotal for quality of life. Societal trends worldwide continue toward increased percent body fat and decreased physical activity with coincident increases in chronic diseases including cardiovascular disease as the top global cause of death along with insulin resistance, accelerated aging, cancer. Although long-term survival rates for cardiovascular disease patients are grim, intense research efforts continue to improve both prevention and treatment options. Pharmacological interventions remain the predominant interventional strategy for mitigating progression and managing symptoms, but cellular therapies have the potential to cure or even mediate remission of cardiovascular disease. Adult stem cells are the most studied cellular therapy in both preclinical and clinical investigation. This review will focus on the advanced therapeutic strategies to augment products and methods of delivery, which many think heralds the future of clinical investigations. Advanced preclinical strategies using adult stem cells are examined to promote synergism between preclinical and clinical research, streamline implementation, and improve this imminent matter of the heart.
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Affiliation(s)
- Kathleen M Broughton
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA
| | - Mark A Sussman
- From the Department of Biology, San Diego State University Heart Institute and the Integrated Regenerative Research Institute, CA.
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38
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Marbán E. A mechanistic roadmap for the clinical application of cardiac cell therapies. Nat Biomed Eng 2018; 2:353-361. [PMID: 30740264 DOI: 10.1038/s41551-018-0216-z] [Citation(s) in RCA: 69] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The development of cells for regenerative therapy has encountered many pitfalls on its path to clinical translation. In cardiology, clinical studies of heart-targeted cell therapies began two decades ago, yet progress towards reaching an approved product has been slow. In this Perspective, I provide an overview of recent cardiac cell therapies, with a focus on the hurdles limiting the translation of cell products from research laboratories to clinical practice. By focusing on heart failure as a target indication, I argue that strategies for overcoming limitations in clinical translation require an increasing emphasis on mechanism-supported efficacy, rather than on phenomenological observations. As research progresses from cells to paracrine mechanisms to defined factors, identifying those defined factors that are involved in achieving superior therapeutic efficacy will better inform the use of cells as therapeutic candidates. The next generation of cell-free biologics may provide the benefits of cell therapy without the intrinsic limitations of whole-cell products.
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Affiliation(s)
- Eduardo Marbán
- Smidt Heart Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.
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Abstract
Mesenchymal stromal cells (MSCs) have been the subject of clinical trials for more than a generation, and the outcomes of advanced clinical trials have fallen short of expectations raised by encouraging pre-clinical animal data in a wide array of disease models. In this Perspective, important biological and pharmacological disparities in pre-clinical research and human translational studies are highlighted, and analyses of clinical trial failures and recent successes provide a rational pathway to MSC regulatory approval and deployment for disorders with unmet medical needs.
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Affiliation(s)
- Jacques Galipeau
- Department of Medicine and Carbone Cancer Center, University of Wisconsin in Madison, Madison, WI, USA.
| | - Luc Sensébé
- UMR5273 STROMALab CNRS/EFS/UPS - INSERM U1031, Toulouse, France.
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40
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Bartunek J, Terzic A, Behfar A, Wijns W. Clinical Experience With Regenerative Therapy in Heart Failure: Advancing Care With Cardiopoietic Stem Cell Interventions. Circ Res 2018; 122:1344-1346. [PMID: 29748365 PMCID: PMC6089255 DOI: 10.1161/circresaha.118.312753] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
Adoption of regenerative strategies for heart failure is challenged by mixed outcomes in clinical trials. Ongoing development plans strive to improve biotherapeutic potency, optimize delivery, standardize dosing, and target responsive patient populations. The Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART) program offers advanced experience in clinical development of next generation regenerative therapies.
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Affiliation(s)
- Jozef Bartunek
- From the Cardiovascular Center, OLV Hospital, Aalst, Belgium (J.B.)
| | - Andre Terzic
- Department of Cardiovascular Medicine and Center for Regenerative Medicine, Rochester, MN (A.T., A.B.)
| | - Atta Behfar
- Department of Cardiovascular Medicine and Center for Regenerative Medicine, Rochester, MN (A.T., A.B.)
| | - William Wijns
- Lambe Institute for Translational Medicine, Curam, National University of Ireland Galway, Saolta University Healthcare Group (W.W.)
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41
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Madigan M, Atoui R. Therapeutic Use of Stem Cells for Myocardial Infarction. Bioengineering (Basel) 2018; 5:bioengineering5020028. [PMID: 29642402 PMCID: PMC6027340 DOI: 10.3390/bioengineering5020028] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2018] [Revised: 03/29/2018] [Accepted: 04/04/2018] [Indexed: 12/15/2022] Open
Abstract
Myocardial infarction is a leading cause of morbidity and mortality worldwide. Although medical and surgical treatments can significantly improve patient outcomes, no treatment currently available is able to generate new contractile tissue or reverse ischemic myocardium. Driven by the recent/novel understanding that regenerative processes do exist in the myocardium—tissue previously thought not to possess regenerative properties—the use of stem cells has emerged as a promising therapeutic approach with high expectations. The literature describes the use of cells from various sources, categorizing them as either embryonic, induced pluripotent, or adult/tissue stem cells (mesenchymal, hematopoietic, skeletal myoblasts, cardiac stem cells). Many publications show the successful use of these cells to regenerate damaged myocardium in both animal and human models; however, more studies are needed to directly compare cells of various origins in efforts to draw conclusions on the ideal source. Although numerous challenges exist in this developing area of research and clinical practice, prospects are encouraging. The following aims to provide a concise review outlining the different types of stem cells used in patients after myocardial infarction.
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Affiliation(s)
- Mariah Madigan
- Northern Ontario School of Medicine, Sudbury, ON P3E 2C6, Canada.
| | - Rony Atoui
- Health Sciences North, Sudbury, ON P3E 5J1, Canada.
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Povsic TJ. Emerging Therapies for Congestive Heart Failure. Clin Pharmacol Ther 2017; 103:77-87. [DOI: 10.1002/cpt.913] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2017] [Revised: 10/06/2017] [Accepted: 10/06/2017] [Indexed: 01/02/2023]
Affiliation(s)
- Thomas J. Povsic
- Duke Clinical Research Institute; Duke University Medical Center; Durham North Carolina USA
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43
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Emami A, Ebner N, von Haehling S. Publishing in a heart failure journal-where lies the scientific interest? ESC Heart Fail 2017; 4:389-401. [PMID: 29131547 PMCID: PMC5695188 DOI: 10.1002/ehf2.12233] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2017] [Accepted: 10/06/2017] [Indexed: 01/09/2023] Open
Affiliation(s)
- Amir Emami
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, D-37075, Göttingen, Germany
| | - Nicole Ebner
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, D-37075, Göttingen, Germany
| | - Stephan von Haehling
- Department of Cardiology and Pneumology, University of Göttingen Medical Center, Robert-Koch-Strasse 40, D-37075, Göttingen, Germany
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44
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Tang J, Cui X, Caranasos TG, Hensley MT, Vandergriff AC, Hartanto Y, Shen D, Zhang H, Zhang J, Cheng K. Heart Repair Using Nanogel-Encapsulated Human Cardiac Stem Cells in Mice and Pigs with Myocardial Infarction. ACS NANO 2017; 11:9738-9749. [PMID: 28929735 PMCID: PMC5656981 DOI: 10.1021/acsnano.7b01008] [Citation(s) in RCA: 112] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/13/2017] [Accepted: 09/01/2017] [Indexed: 05/20/2023]
Abstract
Stem cell transplantation is currently implemented clinically but is limited by low retention and engraftment of transplanted cells and the adverse effects of inflammation and immunoreaction when allogeneic or xenogeneic cells are used. Here, we demonstrate the safety and efficacy of encapsulating human cardiac stem cells (hCSCs) in thermosensitive poly(N-isopropylacrylamine-co-acrylic acid) or P(NIPAM-AA) nanogel in mouse and pig models of myocardial infarction (MI). Unlike xenogeneic hCSCs injected in saline, injection of nanogel-encapsulated hCSCs does not elicit systemic inflammation or local T cell infiltrations in immunocompetent mice. In mice and pigs with acute MI, injection of encapsulated hCSCs preserves cardiac function and reduces scar sizes, whereas injection of hCSCs in saline has an adverse effect on heart healing. In conclusion, thermosensitive nanogels can be used as a stem cell carrier: the porous and convoluted inner structure allows nutrient, oxygen, and secretion diffusion but can prevent the stem cells from being attacked by immune cells.
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Affiliation(s)
- Junnan Tang
- Department
of Cardiology, The First Affiliated Hospital
of Zhengzhou University, Zhengzhou, Henan 450052, China
- Department
of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States
- Department
of Biomedical Engineering, University of
North Carolina at Chapel Hill & North Carolina State University, Raleigh, North Carolina 27607, United States
| | - Xiaolin Cui
- School
of Chemical Engineering, The University
of Adelaide, Adelaide, SA 5005, Australia
| | - Thomas G. Caranasos
- Division
of Cardiothoracic Surgery, University of
North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
| | - M. Taylor Hensley
- Department
of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States
- Department
of Biomedical Engineering, University of
North Carolina at Chapel Hill & North Carolina State University, Raleigh, North Carolina 27607, United States
| | - Adam C. Vandergriff
- Department
of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States
- Department
of Biomedical Engineering, University of
North Carolina at Chapel Hill & North Carolina State University, Raleigh, North Carolina 27607, United States
| | - Yusak Hartanto
- School
of Chemical Engineering, The University
of Adelaide, Adelaide, SA 5005, Australia
| | - Deliang Shen
- Department
of Cardiology, The First Affiliated Hospital
of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Hu Zhang
- School
of Chemical Engineering, The University
of Adelaide, Adelaide, SA 5005, Australia
| | - Jinying Zhang
- Department
of Cardiology, The First Affiliated Hospital
of Zhengzhou University, Zhengzhou, Henan 450052, China
| | - Ke Cheng
- Department
of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, North Carolina 27607, United States
- Department
of Biomedical Engineering, University of
North Carolina at Chapel Hill & North Carolina State University, Raleigh, North Carolina 27607, United States
- Pharmacoengineering
and Molecular Pharmaceutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599, United States
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Affiliation(s)
- Alayn Govea
- Department of Medicine, University of California-San Francisco, San Francisco, California
| | - Randall J. Lee
- Department of Medicine, University of California-San Francisco, San Francisco, California
- Cardiovascular Research Institute, University of California-San Francisco, San Francisco, California
- Institute for Regeneration Medicine, University of California-San Francisco, San Francisco, California
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Abstract
INTRODUCTION Over the past decade, it has become clear that long-term engraftment of any ex vivo expanded cell product transplanted into injured myocardium is modest and all therapeutic regeneration is mediated by stimulation of endogenous repair rather than differentiation of transplanted cells into working myocardium. Given that increasing the retention of transplanted cells boosts myocardial function, focus on the fundamental mechanisms limiting retention and survival of transplanted cells may enable strategies to help to restore normal cardiac function. Areas covered: This review outlines the challenges confronting cardiac engraftment of ex vivo expanded cells and explores means of enhancing cell-mediated repair of injured myocardium. Expert opinion: Stem cell therapy has already come a long way in terms of regenerating damaged hearts though the poor retention of transplanted cells limits the full potential of truly cardiotrophic cell products. Multifaceted strategies directed towards fundamental mechanisms limiting the long-term survival of transplanted cells will be needed to enhance transplanted cell retention and cell-mediated repair of damaged myocardium for cardiac cell therapy to reach its full potential.
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Affiliation(s)
| | - Darryl R Davis
- a University of Ottawa Heart Institute , Ottawa , ON , Canada
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47
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Gray A, McQuillan C, Menown IBA. Advances in Clinical Cardiology 2016: A Summary of the Key Clinical Trials. Adv Ther 2017; 34:1503-1527. [PMID: 28537000 PMCID: PMC5504210 DOI: 10.1007/s12325-017-0560-5] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/10/2017] [Indexed: 12/19/2022]
Abstract
INTRODUCTION The findings of many new cardiology clinical trials over the last year have been published or presented at major international meetings. This paper aims to describe and place in context a summary of the key clinical trials in cardiology presented between January and December 2016. METHODS The authors reviewed clinical trials presented at major cardiology conferences during 2016 including the American College of Cardiology (ACC), European Association for Percutaneous Cardiovascular Interventions (EuroPCR), European Society of Cardiology (ESC), European Association for the Study of Diabetes (EASD), Transcatheter Cardiovascular Therapeutics (TCT), and the American Heart Association (AHA). Selection criteria were trials with a broad relevance to the cardiology community and those with potential to change current practice. RESULTS A total of 57 key cardiology clinical trials were identified for inclusion. Here we describe and place in clinical context the key findings of new data relating to interventional and structural cardiology including delayed stenting following primary angioplasty, contrast-induced nephropathy, management of jailed wires, optimal duration of dual antiplatelet therapy (DAPT), stenting vs bypass for left main disease, new generation stents (BioFreedom, Orsiro, Absorb), transcatheter aortic valve implantation (Edwards Sapien XT, transcatheter embolic protection), and closure devices (Watchman, Amplatzer). New preventative cardiology data include trials of bariatric surgery, empagliflozin, liraglutide, semaglutide, PCSK9 inhibitors (evolocumab and alirocumab), and inclisiran. Antiplatelet therapy trials include platelet function monitoring and ticagrelor vs clopidogrel for peripheral vascular disease. New data are also presented in fields of heart failure (sacubitril/valsartan, aliskiren, spironolactone), atrial fibrillation (rivaroxaban in patients undergoing coronary intervention, edoxaban in DC cardioversion), cardiac devices (implantable cardioverter defibrillator in non-ischemic cardiomyopathy), and electrophysiology (cryoballoon vs radiofrequency ablation). CONCLUSION This paper presents a summary of key clinical cardiology trials during the past year and should be of practical value to both clinicians and cardiology researchers.
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Affiliation(s)
- Alastair Gray
- Craigavon Cardiac Centre, Southern Trust, Craigavon, Northern Ireland, UK
| | - Conor McQuillan
- Craigavon Cardiac Centre, Southern Trust, Craigavon, Northern Ireland, UK
| | - Ian B A Menown
- Craigavon Cardiac Centre, Southern Trust, Craigavon, Northern Ireland, UK.
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Teerlink JR, Metra M, Filippatos GS, Davison BA, Bartunek J, Terzic A, Gersh BJ, Povsic TJ, Henry TD, Alexandre B, Homsy C, Edwards C, Seron A, Wijns W, Cotter G. Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) study. Eur J Heart Fail 2017; 19:1520-1529. [PMID: 28560782 DOI: 10.1002/ejhf.898] [Citation(s) in RCA: 71] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2017] [Revised: 04/26/2017] [Accepted: 04/28/2017] [Indexed: 12/24/2022] Open
Abstract
AIMS Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone-marrow-derived, lineage-directed, autologous cardiopoietic mesenchymal stem cells (C3BS-CQR-1) on LV remodelling in patients with advanced HF enrolled in the CHART-1 study. METHODS AND RESULTS Patients (n=351) with symptomatic advanced HF secondary to ischaemic heart disease, and reduced LV ejection fraction (LVEF <35%) were randomized to receive C3BS-CQR-1 or a sham procedure. In a post hoc analysis we examined the effect of C3BS-CQR-1 on LV reverse remodelling within 1 year of the procedure and the influence of C3BS-CQR-1 dosing in the 271 patients treated as randomized. Delivery of C3BS-CQR-1 was associated with a progressive decrease in both LV end-diastolic volume (LVEDV) and end-systolic volume (LVESV) within 52 weeks after treatment. At 1 year, the LVEDV and LVESV of treated patients decreased by 17.0 mL and 12.8 mL greater than controls (P=0.006 and P=0.017, respectively). The effect on LVEDV was maintained after multivariable adjustment for baseline age, systolic blood pressure, LVEDV, LVEF and history of myocardial infarction. The largest reverse remodelling was evident in the patients receiving a moderate number of injections (<20). CONCLUSION In CHART-1, intramyocardial administration of cardiopoietic stem cells led to reverse remodelling as evidenced by significant progressive decreases in LVEDV and LVESV through the 52 weeks of follow-up. Further studies are needed to explore the dose response with regard to cell number and injected volume, and reverse remodelling.
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Affiliation(s)
- John R Teerlink
- School of Medicine, University of California San Francisco and Section of Cardiology, San Francisco Veterans Affairs Medical Center, San Francisco, CA, USA
| | - Marco Metra
- Cardiology, Department of Medical and Surgical Specialties, Radiological Sciences, and Public Health, University and Spedali Civili, Brescia, Italy
| | - Gerasimos S Filippatos
- National and Kapodistrian University of Athens, School of Medicine, Attikon University Hospital, Athens, Greece
| | | | | | - Andre Terzic
- Department of Cardiovascular Diseases, Mayo Clinic, Center for Regenerative Medicine, Rochester, MN, USA
| | - Bernard J Gersh
- Department of Cardiovascular Diseases, Mayo Clinic, Center for Regenerative Medicine, Rochester, MN, USA
| | - Thomas J Povsic
- Duke Clinical Research Institute and Duke Medicine, Durham, NC, USA
| | | | | | | | | | | | - William Wijns
- Cardiovascular Centre, OLV Hospital, Aalst, Belgium.,The Lambe Institute for Translational Medicine and Curam, National University of Ireland Galway and Saolta University Healthcare Group, Galway, Ireland
| | - Gad Cotter
- Momentum Research, Inc., Durham, NC, USA
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Beltrami AP, Madeddu P. Pericytes and cardiac stem cells: Common features and peculiarities. Pharmacol Res 2017; 127:101-109. [PMID: 28578204 DOI: 10.1016/j.phrs.2017.05.023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/08/2017] [Revised: 05/14/2017] [Accepted: 05/25/2017] [Indexed: 12/20/2022]
Abstract
Clinical data and basic research indicate that the structural and functional alterations that characterize the evolution of cardiac disease towards heart failure may be, at least in part, reversed. This paradigm shift is due to the accumulation of evidence indicating that, in peculiar settings, cardiomyocytes may be replenished. Moving from the consideration that cardiomyocytes are rapidly withdrawn from the cell cycle after birth, independent laboratories have tested the hypothesis that cardiac resident stem/progenitor cells resided in mammalian hearts and were important for myocardial repair. After almost two decades of intensive investigation, several (but partially overlapping) cardiac resident stem/progenitor cell populations have been identified. These primitive cells are characterized by mesenchymal features, unique properties that distinguish them from mesodermal progenitors residing in other tissues, and heterogeneous embryological origins (that include the neural crest and the epicardium). A further layer of complexity is related to the nature, in vivo localization and properties of mesodermal progenitors residing in adult tissues. Intriguingly, these latter, whose possible perivascular pericyte/mural cell origin has been shown, have been identified in human hearts too. However, their exact anatomical localization, pathophysiological role, and their relationship with cardiac stem/progenitor cells are emerging only recently. Therefore, aim of this review is to discuss the different origin, the distinct nature, and the complementary effect of cardiac stem cells and pericytes supporting regenerative strategies based on the combined use of both myogenic and angiogenic factors.
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Affiliation(s)
- Antonio Paolo Beltrami
- Istituto di Anatomia Patologica, Università degli Studi di Udine, P.zzle S. Maria della Misericordia, 33100 Udine, Italy.
| | - Paolo Madeddu
- Experimental Cardiovascular Medicine, Regenerative Medicine Section, Bristol Heart Institute, School of Clinical Sciences, University of Bristol, Level 7, Bristol Royal Infirmary, Upper Maudlin Street, Bristol BS2 8HW, United Kingdom.
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50
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Autologous and allogeneic cardiac stem cell therapy for cardiovascular diseases. Pharmacol Res 2017; 127:92-100. [PMID: 28554583 DOI: 10.1016/j.phrs.2017.05.024] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Revised: 04/14/2017] [Accepted: 05/25/2017] [Indexed: 12/27/2022]
Abstract
Stem cell therapy is one of the most promising therapeutic innovations to help restore cardiac structure and function after ischemic insults to the heart. However, phase I and II clinical trials with autologous "first-generation stem cells" have yielded inconsistent results in ischemic cardiomyopathy patients and have not produced the definitive evidence for their broad clinical application. Recently, new cell types such as cardiac stem cells (CSC) and new allogeneic sources have attracted the attention of researchers given their inherent biological, clinical and logistic advantages. Preclinical evidence and emerging clinical data show that exogenous CSC produce a range of protein-based factors that have a powerful cardioprotective effect in the ischemic myocardium, immunoregulatory properties that promote angiogenesis and reduce scar formation, and are able to activate endogenous CSC which multiply and differentiate into cardiomyocytes and microvasculature. Furthermore, allogeneic CSC can be produced in large quantities beforehand and can be administered "off-the-shelf" early during the acute phase of myocardial ischemia. The distinctive immunological behavior of allogeneic CSC and their interaction with the host immune system is supposed to produce immunomodulatory beneficial effects in the short-term, preventing long-term side-effects after their rejection. Preclinical studies have shown highly promising results with allogeneic CSC, and clinical trials are already ongoing. Finally, unraveling questions about the biology and physiology of CSC, the characterization of their secretome, the conduction of larger clinical trials with autologous CSC, the definitive evidence on the safety and efficacy of allogeneic CSC in humans and the possibility of repeated administrations or combinations with other cell types and soluble factors will pave the road for further developments with CSC, that will undoubtedly determine the future of cardiovascular regenerative medicine in human beings.
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