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Xu Y, Yu Y, Guo Z. Hydrogels in cardiac tissue engineering: application and challenges. Mol Cell Biochem 2025; 480:2201-2222. [PMID: 39495368 DOI: 10.1007/s11010-024-05145-3] [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: 07/05/2024] [Accepted: 10/18/2024] [Indexed: 11/05/2024]
Abstract
Cardiovascular disease remains the leading cause of global mortality. Current stem cell therapy and heart transplant therapy have limited long-term stability in cardiac function. Cardiac tissue engineering may be one of the key methods for regenerating damaged myocardial tissue. As an ideal scaffold material, hydrogel has become a viable tissue engineering therapy for the heart. Hydrogel can not only provide mechanical support for infarcted myocardium but also serve as a carrier for various drugs, bioactive factors, and cells to increase myocardial contractility and improve the cell microenvironment in the infarcted area, thereby improving cardiac function. This paper reviews the applications of hydrogels and biomedical mechanisms in cardiac tissue engineering and discusses the challenge of clinical transformation of hydrogel in cardiac tissue engineering, providing new strategies for treating cardiovascular diseases.
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Affiliation(s)
- Yaping Xu
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People's Hospital, Henan, 450016, Zhengzhou, People's Republic of China
| | - Yuexin Yu
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People's Hospital, Henan, 450016, Zhengzhou, People's Republic of China
| | - Zhikun Guo
- Henan Key Laboratory of Cardiac Remodeling and Transplantation, Zhengzhou Seventh People's Hospital, Henan, 450016, Zhengzhou, People's Republic of China.
- Henan Key Laboratory of Medical Tissue Regeneration, Xinxiang Medical University, Xinxiang, 453003, Henan, People's Republic of China.
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Fiorino E, Rossin D, Vanni R, Aubry M, Giachino C, Rastaldo R. Recent Insights into Endogenous Mammalian Cardiac Regeneration Post-Myocardial Infarction. Int J Mol Sci 2024; 25:11747. [PMID: 39519298 PMCID: PMC11546116 DOI: 10.3390/ijms252111747] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 10/29/2024] [Accepted: 10/30/2024] [Indexed: 11/16/2024] Open
Abstract
Myocardial infarction (MI) is a critical global health issue and a leading cause of heart failure. Indeed, while neonatal mammals can regenerate cardiac tissue mainly through cardiomyocyte proliferation, this ability is lost shortly after birth, resulting in the adult heart's inability to regenerate after injury effectively. In adult mammals, the adverse cardiac remodelling, which compensates for the loss of cardiac cells, impairs cardiac function due to the non-contractile nature of fibrotic tissue. Moreover, the neovascularisation after MI is inadequate to restore blood flow to the infarcted myocardium. This review aims to synthesise the most recent insights into the molecular and cellular players involved in endogenous myocardial and vascular regeneration, facilitating the identification of mechanisms that could be targeted to trigger cardiac regeneration, reduce fibrosis, and improve functional recovery post-MI. Reprogramming adult cardiomyocytes to regain their proliferative potential, along with the modulation of target cells responsible for neovascularisation, represents promising therapeutic strategies. An updated overview of endogenous mechanisms that regulate both myocardial and coronary vasculature regeneration-including stem and progenitor cells, growth factors, cell cycle regulators, and key signalling pathways-could help identify new critical intervention points for therapeutic applications.
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Affiliation(s)
| | | | | | | | | | - Raffaella Rastaldo
- Department of Clinical and Biological Sciences, University of Turin, Regione Gonzole 10, 10043 Orbassano, Italy; (E.F.); (D.R.); (R.V.); (M.A.); (C.G.)
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Jiang Z, Yu J, Zhou H, Feng J, Xu Z, Wan M, Zhang W, He Y, Jia C, Shao S, Guo H, Liu B. Research hotspots and emerging trends of mesenchymal stem cells in cardiovascular diseases: a bibliometric-based visual analysis. Front Cardiovasc Med 2024; 11:1394453. [PMID: 38873270 PMCID: PMC11169657 DOI: 10.3389/fcvm.2024.1394453] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 05/17/2024] [Indexed: 06/15/2024] Open
Abstract
Background Mesenchymal stem cells (MSCs) have important research value and broad application prospects in cardiovascular diseases (CVDs). However, few bibliometric analyses on MSCs in cardiovascular diseases are available. This study aims to provide a thorough review of the cooperation and influence of countries, institutions, authors, and journals in the field of MSCs in cardiovascular diseases, with the provision of discoveries in the latest progress, evolution paths, frontier research hotspots, and future research trends in the regarding field. Methods The articles related to MSCs in cardiovascular diseases were retrieved from the Web of Science. The bibliometric study was performed by CiteSpace and VOSviewer, and the knowledge map was generated based on data obtained from retrieved articles. Results In our study, a total of 4,852 publications launched before August 31, 2023 were accessed through the Web of Science Core Collection (WoSCC) database via our searching strategy. Significant fluctuations in global publications were observed in the field of MSCs in CVDs. China emerged as the nation with the largest number of publications, yet a shortage of high-quality articles was noted. The interplay among countries, institutions, journals and authors is visually represented in the enclosed figures. Importantly, current research trends and hotspots are elucidated. Cluster analysis on references has highlighted the considerable interest in exosomes, extracellular vesicles, and microvesicles. Besides, keywords analysis revealed a strong emphasis on myocardial infarction, therapy, and transplantation. Treatment methods-related keywords were prominent, while keywords associated with extracellular vesicles gathered significant attention from the long-term perspective. Conclusion MSCs in CVDs have become a topic of active research interest, showcasing its latent value and potential. By summarizing the latest progress, identifying the research hotspots, and discussing the future trends in the advancement of MSCs in CVDs, we aim to offer valuable insights for considering research prospects.
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Affiliation(s)
- Zhihang Jiang
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiajing Yu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Houle Zhou
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiaming Feng
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Zehui Xu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Melisandre Wan
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Weiwei Zhang
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Yuqing He
- Department of Preventive Medicine, College of Public Health, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Chengyao Jia
- Guanghua School of Stomatology, Sun Yat-Sen University, Guangzhou, China
| | - Shuijin Shao
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Haidong Guo
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Baonian Liu
- Department of Anatomy, School of Chinese Integrative Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Berezin OO, Berezina TA, Hoppe UC, Lichtenauer M, Berezin AE. Diagnostic and predictive abilities of myokines in patients with heart failure. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2024; 142:45-98. [PMID: 39059994 DOI: 10.1016/bs.apcsb.2023.12.021] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/28/2024]
Abstract
Myokines are defined as a heterogenic group of numerous cytokines, peptides and metabolic derivates, which are expressed, synthesized, produced, and released by skeletal myocytes and myocardial cells and exert either auto- and paracrine, or endocrine effects. Previous studies revealed that myokines play a pivotal role in mutual communications between skeletal muscles, myocardium and remote organs, such as brain, vasculature, bone, liver, pancreas, white adipose tissue, gut, and skin. Despite several myokines exert complete divorced biological effects mainly in regulation of skeletal muscle hypertrophy, residential cells differentiation, neovascularization/angiogenesis, vascular integrity, endothelial function, inflammation and apoptosis/necrosis, attenuating ischemia/hypoxia and tissue protection, tumor growth and malignance, for other occasions, their predominant effects affect energy homeostasis, glucose and lipid metabolism, adiposity, muscle training adaptation and food behavior. Last decade had been identified 250 more myokines, which have been investigating for many years further as either biomarkers or targets for heart failure management. However, only few myokines have been allocated to a promising tool for monitoring adverse cardiac remodeling, ischemia/hypoxia-related target-organ dysfunction, microvascular inflammation, sarcopenia/myopathy and prediction for poor clinical outcomes among patients with HF. This we concentrate on some most plausible myokines, such as myostatin, myonectin, brain-derived neurotrophic factor, muslin, fibroblast growth factor 21, irisin, leukemia inhibitory factor, developmental endothelial locus-1, interleukin-6, nerve growth factor and insulin-like growth factor-1, which are suggested to be useful biomarkers for HF development and progression.
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Affiliation(s)
- Oleksandr O Berezin
- Luzerner Psychiatrie AG, Department of Senior Psychiatrie, St. Urban, Switzerland
| | - Tetiana A Berezina
- Department of Internal Medicine and Nephrology, VitaCenter, Zaporozhye, Ukraine
| | - Uta C Hoppe
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University, Salzburg, Austria
| | - Michael Lichtenauer
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University, Salzburg, Austria
| | - Alexander E Berezin
- Department of Internal Medicine II, Division of Cardiology, Paracelsus Medical University, Salzburg, Austria.
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Castillo-Casas JM, Caño-Carrillo S, Sánchez-Fernández C, Franco D, Lozano-Velasco E. Comparative Analysis of Heart Regeneration: Searching for the Key to Heal the Heart-Part II: Molecular Mechanisms of Cardiac Regeneration. J Cardiovasc Dev Dis 2023; 10:357. [PMID: 37754786 PMCID: PMC10531542 DOI: 10.3390/jcdd10090357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Revised: 08/18/2023] [Accepted: 08/22/2023] [Indexed: 09/28/2023] Open
Abstract
Cardiovascular diseases are the leading cause of death worldwide, among which ischemic heart disease is the most representative. Myocardial infarction results from occlusion of a coronary artery, which leads to an insufficient blood supply to the myocardium. As it is well known, the massive loss of cardiomyocytes cannot be solved due the limited regenerative ability of the adult mammalian hearts. In contrast, some lower vertebrate species can regenerate the heart after an injury; their study has disclosed some of the involved cell types, molecular mechanisms and signaling pathways during the regenerative process. In this 'two parts' review, we discuss the current state-of-the-art of the main response to achieve heart regeneration, where several processes are involved and essential for cardiac regeneration.
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Affiliation(s)
- Juan Manuel Castillo-Casas
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
| | - Sheila Caño-Carrillo
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
| | - Cristina Sánchez-Fernández
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
- Medina Foundation, 18007 Granada, Spain
| | - Diego Franco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
- Medina Foundation, 18007 Granada, Spain
| | - Estefanía Lozano-Velasco
- Cardiovascular Development Group, Department of Experimental Biology, University of Jaén, 23071 Jaén, Spain; (J.M.C.-C.); (S.C.-C.); (C.S.-F.); (D.F.)
- Medina Foundation, 18007 Granada, Spain
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Macêdo Ferreira Santos LD, Cardim Barreto B, Costa Quadros H, Santana Meira C, Siqueira Ferraz-Carvalho RD, Souza Rebouças JD, Garcia Macambira S, Fraga Vasconcelos J, Freitas Souza BSD, Botelho Pereira Soares M, Stela Santos-Magalhães N, Rocha Formiga F. Tissue response and retention of micro- and nanosized liposomes in infarcted mice myocardium after ultrasound-guided transthoracic injection. Eur J Pharm Biopharm 2022; 173:141-149. [DOI: 10.1016/j.ejpb.2022.03.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2021] [Revised: 01/19/2022] [Accepted: 03/14/2022] [Indexed: 12/16/2022]
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Gonciar D, Mocan T, Agoston-Coldea L. Nanoparticles Targeting the Molecular Pathways of Heart Remodeling and Regeneration. Pharmaceutics 2022; 14:pharmaceutics14040711. [PMID: 35456545 PMCID: PMC9028351 DOI: 10.3390/pharmaceutics14040711] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/13/2022] [Accepted: 03/22/2022] [Indexed: 12/10/2022] Open
Abstract
Cardiovascular diseases are the main cause of death worldwide, a trend that will continue to grow over the next decade. The heart consists of a complex cellular network based mainly on cardiomyocytes, but also on endothelial cells, smooth muscle cells, fibroblasts, and pericytes, which closely communicate through paracrine factors and direct contact. These interactions serve as valuable targets in understanding the phenomenon of heart remodeling and regeneration. The advances in nanomedicine in the controlled delivery of active pharmacological agents are remarkable and may provide substantial contribution to the treatment of heart diseases. This review aims to summarize the main mechanisms involved in cardiac remodeling and regeneration and how they have been applied in nanomedicine.
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Affiliation(s)
- Diana Gonciar
- 2nd Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca 400000, Romania; (D.G.); (L.A.-C.)
| | - Teodora Mocan
- Physiology Department, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca 400000, Romania
- Department of Nanomedicine, Regional Institute of Gastroenterology and Hepatology, Cluj-Napoca 400162, Romania
- Correspondence:
| | - Lucia Agoston-Coldea
- 2nd Department of Internal Medicine, Faculty of Medicine, “Iuliu Hațieganu” University of Medicine and Pharmacy, Cluj-Napoca 400000, Romania; (D.G.); (L.A.-C.)
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Silpa L, Sim R, Russell AJ. Recent Advances in Small Molecule Stimulation of Regeneration and Repair. Bioorg Med Chem Lett 2022; 61:128601. [PMID: 35123003 DOI: 10.1016/j.bmcl.2022.128601] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/26/2022] [Accepted: 01/28/2022] [Indexed: 11/02/2022]
Abstract
Therapeutic approaches to stimulate regeneration and repair have the potential to transform healthcare and improve outcomes for patients suffering from numerous chronic degenerative diseases. To date most approaches have involved the transplantation of therapeutic cells, and while there have been a small number of clinical approvals, major hurdles exist to the routine adoption of such therapies. In recent years humans and other mammals have been shown to possess a regenerative capacity across multiple tissues and organs, and an innate regenerative and repair response has been shown to be activated in these organs in response to injury. These realisations have inspired a transformative approach in regenerative medicine: the development of new agents to directly target these innate regeneration and repair pathways. In this article we will review the current state of the art in the discovery of small molecule modulators of regeneration and their translation towards therapeutic agents, focussing specifically on the areas of neuroregeneration and cardiac regeneration.
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Affiliation(s)
- Laurence Silpa
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford OX1 3TA
| | - Rachel Sim
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford OX1 3TA
| | - Angela J Russell
- Department of Chemistry, Chemistry Research Laboratory, University of Oxford OX1 3TA; Department of Pharmacology, University of Oxford, University of Oxford OX1 3QT.
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Xiao M, Tang Y, Wang J, Lu G, Niu J, Wang J, Li J, Liu Q, Wang Z, Huang Z, Guo Y, Gao T, Zhang X, Yue S, Gu J. A new FGF1 variant protects against adriamycin-induced cardiotoxicity via modulating p53 activity. Redox Biol 2022; 49:102219. [PMID: 34990928 PMCID: PMC8743227 DOI: 10.1016/j.redox.2021.102219] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2021] [Revised: 12/05/2021] [Accepted: 12/17/2021] [Indexed: 12/17/2022] Open
Abstract
A cumulative and progressively developing cardiomyopathy induced by adriamycin (ADR)-based chemotherapy is a major obstacle for its clinical application. However, there is a lack of safe and effective method to protect against ADR-induced cardiotoxicity. Here, we found that mRNA and protein levels of FGF1 were decreased in ADR-treated mice, primary cardiomyocytes and H9c2 cells, suggesting the potential effect of FGF1 to protect against ADR-induced cardiotoxicity. Then, we showed that treatment with a FGF1 variant (FGF1ΔHBS) with reduced proliferative potency significantly prevented ADR-induced cardiac dysfunction as well as ADR-associated cardiac inflammation, fibrosis, and hypertrophy. The mechanistic study revealed that apoptosis and oxidative stress, the two vital pathological factors in ADR-induced cardiotoxicity, were largely alleviated by FGF1ΔHBS treatment. Furthermore, the inhibitory effects of FGF1ΔHBS on ADR-induced apoptosis and oxidative stress were regulated by decreasing p53 activity through upregulation of Sirt1-mediated p53 deacetylation and enhancement of murine double minute 2 (MDM2)-mediated p53 ubiquitination. Upregulation of p53 expression or cardiac specific-Sirt1 knockout (Sirt1-CKO) almost completely abolished FGF1ΔHBS-induced protective effects in cardiomyocytes. Based on these findings, we suggest that FGF1ΔHBS may be a potential therapeutic agent against ADR-induced cardiotoxicity.
Cardiac expression of FGF1 were decreased by ADR treatment. FGF1ΔHBS prevented ADR-induced cardiac structural abnormalities and dysfunction. FGF1ΔHBS inhibited ADR-induced oxidative stress and apoptosis by deacetylating p53. Deacetylated p53 induced by FGF1ΔHBS accelerated the ubiquitination of p53 by MDM2.
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Affiliation(s)
- Mengjie Xiao
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Yufeng Tang
- Department of Orthopedic Surgery, The First Affiliated Hospital of Shandong First Medical University, Jinan, Shandong, 250014, China
| | - Jie Wang
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Guangping Lu
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jianlou Niu
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jie Wang
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Jiahao Li
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Qingbo Liu
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Zhaoyun Wang
- Department of Neurosurgical Intensive Care Unit & Emergency Neurosurgery, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Zhifeng Huang
- School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yuanfang Guo
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Ting Gao
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Xiaohui Zhang
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Shouwei Yue
- Rehabilitation Center, Qilu Hospital, Cheelo College of Medicine, Shandong University, Jinan, Shandong, 250012, China
| | - Junlian Gu
- School of Nursing and Rehabilitation, Cheeloo College of Medicine, Shandong University, Jinan, Shandong, 250012, China.
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10
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Abstract
Self-assembling peptides (SAPs), which form hydrogels through physical cross-linking of soluble structures, are an intriguing class of materials that have been applied as tissue engineering scaffolds and drug delivery vehicles. For feasible application of these tissue mimetics via minimally invasive delivery, their bulk mechanical properties must be compatible with current delivery strategies. However, injectable SAPs which possess shear-thinning capacity, as well as the ability to reassemble after cessation of shearing can be technically challenging to generate. Many SAPs either clog the high-gauge needle/catheter at high concentration during delivery or are incapable of reassembly following delivery. In this chapter, we provide a detailed protocol for topological control of enzyme-responsive peptide-based hydrogels that enable the user to access both advantages. These materials are formulated as sterically constrained cyclic peptide progelators to temporarily disrupt self-assembly during injection-based delivery, which avoids issues with clogging of needles and catheters as well as nearby vasculature. Proteolytic cleavage by enzymes produced at the target tissue induces progelator linearization and hydrogelation. The scope of this approach is demonstrated by their ability to flow through a catheter without clogging and activated gelation upon exposure to target enzymes.
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Affiliation(s)
- Andrea S Carlini
- Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA
- Department of Materials Science & Engineering, Northwestern University, Evanston, IL, USA
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Department of Pharmacology, Northwestern University, Evanston, IL, USA
- International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA
- Simpson Querrey Institute, Northwestern University, Evanston, IL, USA
| | - Mary F Cassidy
- Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA
- Department of Materials Science & Engineering, Northwestern University, Evanston, IL, USA
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
- Department of Pharmacology, Northwestern University, Evanston, IL, USA
- International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA
- Simpson Querrey Institute, Northwestern University, Evanston, IL, USA
| | - Nathan C Gianneschi
- Department of Chemistry, Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, USA.
- Department of Materials Science & Engineering, Northwestern University, Evanston, IL, USA.
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
- Department of Pharmacology, Northwestern University, Evanston, IL, USA.
- International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA.
- Simpson Querrey Institute, Northwestern University, Evanston, IL, USA.
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Hsu YC, Chung YF, Chen MS, Wang CK, Jiang ST, Chiu IM. Establishing F1A-CreER T2 Mice to Trace Fgf1 Expression in Adult Mouse Cardiomyocytes. Cells 2021; 11:cells11010121. [PMID: 35011683 PMCID: PMC8749990 DOI: 10.3390/cells11010121] [Citation(s) in RCA: 2] [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: 11/13/2021] [Revised: 12/24/2021] [Accepted: 12/25/2021] [Indexed: 01/09/2023] Open
Abstract
Fibroblast growth factor 1 (FGF1) regulates many biological and physiological processes. In mice, Fgf1 gene contains at least three upstream promoters and are alternatively spliced to the first protein coding exon, giving rise to different Fgf1 mRNA variants (1A, 1B and 1G). Among them, the Fgf1A transcript is predominantly expressed in the heart. FGF1 can induce cardiomyocyte regeneration and cardiogenesis in vitro and in vivo. Here, we generated a novel mouse line using the Fgf1A promoter (F1A) driving the expression of the inducible Cre recombinase (CreERT2). We firstly demonstrated that the highest mRNA expression of CreERT2 were detected in the heart specifically of F1A-CreERT2 mice, similar to that of Fgf1A mRNA. The F1A-CreERT2 mice were crossed with ROSA26 mice, and the F1 mice were analyzed. The LacZ-positive signals were detected exclusively in the heart after tamoxifen administration. The CreERT2-mediated recombination in the tissues is monitored through LacZ-positive signals, indicating the in situ localization of F1A-positive cells. Consistently, these F1A-positive cells with RFP-positive signals or LacZ-positive blue signals were co-localized with cardiomyocytes expressing cardiac troponin T, suggesting cardiomyocyte-specific activation of Fgf1A promoter. Our data suggested that the F1A-CreERT2 mouse line could be used for time-dependent and lineage tracing of Fgf1A-expressing cells in vivo.
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Affiliation(s)
- Yi-Chao Hsu
- Institute of Biomedical Sciences, Mackay Medical College, New Taipei City 252, Taiwan;
- Department of Audiology and Speech Language Pathology, Mackay Medical College, New Taipei City 252, Taiwan
| | - Yu-Fen Chung
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 350, Taiwan; (Y.-F.C.); (M.-S.C.)
| | - Mei-Shu Chen
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 350, Taiwan; (Y.-F.C.); (M.-S.C.)
| | - Chi-Kuang Wang
- Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Tainan 700, Taiwan; (C.-K.W.); (S.-T.J.)
| | - Si-Tse Jiang
- Department of Research and Development, National Laboratory Animal Center, National Applied Research Laboratories, Tainan 700, Taiwan; (C.-K.W.); (S.-T.J.)
| | - Ing-Ming Chiu
- Institute of Cellular and System Medicine, National Health Research Institutes, Miaoli 350, Taiwan; (Y.-F.C.); (M.-S.C.)
- Department of Life Sciences, National Chung Hsing University, Taichung 400, Taiwan
- Department of Internal Medicine, The Ohio State University, Columbus, OH 43210, USA
- Correspondence: ; Tel.: +886-37-206-166 (ext. 37500); Fax: +886-37-587-408
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Tajabadi M, Goran Orimi H, Ramzgouyan MR, Nemati A, Deravi N, Beheshtizadeh N, Azami M. Regenerative strategies for the consequences of myocardial infarction: Chronological indication and upcoming visions. Biomed Pharmacother 2021; 146:112584. [PMID: 34968921 DOI: 10.1016/j.biopha.2021.112584] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Revised: 12/20/2021] [Accepted: 12/21/2021] [Indexed: 12/13/2022] Open
Abstract
Heart muscle injury and an elevated troponin level signify myocardial infarction (MI), which may result in defective and uncoordinated segments, reduced cardiac output, and ultimately, death. Physicians apply thrombolytic therapy, coronary artery bypass graft (CABG) surgery, or percutaneous coronary intervention (PCI) to recanalize and restore blood flow to the coronary arteries, albeit they were not convincingly able to solve the heart problems. Thus, researchers aim to introduce novel substitutional therapies for regenerating and functionalizing damaged cardiac tissue based on engineering concepts. Cell-based engineering approaches, utilizing biomaterials, gene, drug, growth factor delivery systems, and tissue engineering are the most leading studies in the field of heart regeneration. Also, understanding the primary cause of MI and thus selecting the most efficient treatment method can be enhanced by preparing microdevices so-called heart-on-a-chip. In this regard, microfluidic approaches can be used as diagnostic platforms or drug screening in cardiac disease treatment. Additionally, bioprinting technique with whole organ 3D printing of human heart with major vessels, cardiomyocytes and endothelial cells can be an ideal goal for cardiac tissue engineering and remarkable achievement in near future. Consequently, this review discusses the different aspects, advancements, and challenges of the mentioned methods with presenting the advantages and disadvantages, chronological indications, and application prospects of various novel therapeutic approaches.
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Affiliation(s)
- Maryam Tajabadi
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16844, Iran
| | - Hanif Goran Orimi
- School of Metallurgy and Materials Engineering, Iran University of Science and Technology (IUST), Narmak, Tehran 16844, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Maryam Roya Ramzgouyan
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Alireza Nemati
- Department of Biomedical Engineering, Amirkabir University of Technology (Tehran Polytechnic), Tehran, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Niloofar Deravi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Nima Beheshtizadeh
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Mahmoud Azami
- Department of Tissue Engineering, School of Advanced Technologies in Medicine, Tehran University of Medical Sciences, Iran; Regenerative Medicine Group (REMED), Universal Scientific Education and Research Network (USERN), Tehran, Iran.
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Exogenous extracellular matrix proteins decrease cardiac fibroblast activation in stiffening microenvironment through CAPG. J Mol Cell Cardiol 2021; 159:105-119. [PMID: 34118218 PMCID: PMC10066715 DOI: 10.1016/j.yjmcc.2021.06.001] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 06/04/2021] [Accepted: 06/07/2021] [Indexed: 11/20/2022]
Abstract
Controlling fibrosis is an essential part of regenerating the post-ischemic heart. In the post-ischemic heart, fibroblasts differentiate to myofibroblasts that produce collagen-rich matrix to physically stabilize the infarct area. Infarct models in adult mice result in permanent scarring unlike newborn animals which fully regenerate. Decellularized extracellular matrix (dECM) hydrogels derived from early-aged hearts have been shown to be a transplantable therapy that preserves heart function and stimulates cardiomyocyte proliferation and vascularization. In this study, we investigate the anti-fibrotic effects of injectable dECM hydrogels in a cardiac explant model in the context of age-associated tissue compliance. Treatments with adult and fetal dECM hydrogels were tested for molecular effects on cardiac fibroblast activation and fibrosis. Altered sensitivity of fibroblasts to the mechanosignaling of the remodeling microenvironment was evaluated by manipulating the native extracellular matrix in explants and also with elastomeric substrates in the presence of dECM hydrogels. The injectable fetal dECM hydrogel treatment decreases fibroblast activation and contractility and lowers the stiffness-mediated increases in fibroblast activation observed in stiffened explants. The anti-fibrotic effect of dECM hydrogel is most observable at highest stiffness. Experiments with primary cells on elastomeric substrates with dECM treatment support this phenomenon. Transcriptome analysis indicated that dECM hydrogels affect cytoskeleton related signaling including Macrophage capping protein (CAPG) and Leupaxin (LPXN). CAPG was down-regulated by the fetal dECM hydrogel. LPXN expression was decreased by stiffening the explants; however, this effect was reversed by dECM hydrogel treatment. Pharmacological disruption of cytoskeleton polymerization lowered fibroblast activation and CAPG levels. Knocking down CAPG expression with siRNA inhibited fibroblast activation and collagen deposition. Collectively, fibroblast activation is dependent on cooperative action of extracellular molecular signals and mechanosignaling by cytoskeletal integrity.
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Alvi SB, Ahmed S, Sridharan D, Naseer Z, Pracha N, Wang H, Boudoulas KD, Zhu W, Sayed N, Khan M. De novo Drug Delivery Modalities for Treating Damaged Hearts: Current Challenges and Emerging Solutions. Front Cardiovasc Med 2021; 8:742315. [PMID: 34651028 PMCID: PMC8505729 DOI: 10.3389/fcvm.2021.742315] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 08/31/2021] [Indexed: 11/13/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of mortality, resulting in approximately one-third of deaths worldwide. Among CVD, acute myocardial infarctions (MI) is the leading cause of death. Current treatment modalities for treating CVD have improved over the years, but the demand for new and innovative therapies has been on the rise. The field of nanomedicine and nanotechnology has opened a new paradigm for treating damaged hearts by providing improved drug delivery methods, specifically targeting injured areas of the myocardium. With the advent of innovative biomaterials, newer therapeutics such as growth factors, stem cells, and exosomes have been successfully delivered to the injured myocardial tissue, promoting improvement in cardiac function. This review focuses on three major drug delivery modalities: nanoparticles, microspheres, and hydrogels, and their potential for treating damaged hearts following an MI.
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Affiliation(s)
- Syed Baseeruddin Alvi
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
| | - Salmman Ahmed
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
| | - Divya Sridharan
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
| | - Zahra Naseer
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
| | - Nooruddin Pracha
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
| | - Henry Wang
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
| | - Konstantinos Dean Boudoulas
- Division of Cardiovascular Medicine, Department of Medicine, The Ohio State University Wexner Medical Center, Columbus, OH, United States
| | - Wuqiang Zhu
- Department of Cardiovascular Diseases, Physiology and Biomedical Engineering, Mayo Clinic, Phoenix, AZ, United States
| | - Nazish Sayed
- Division of Vascular Surgery, Department of Surgery, The Stanford Cardiovascular Institute, Stanford University, Stanford, CA, United States
| | - Mahmood Khan
- Department of Emergency Medicine, The Ohio State University Wexner Medical Center, Davis Heart and Lung Research Institute, College of Medicine, Columbus, OH, United States
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Khosravi F, Ahmadvand N, Bellusci S, Sauer H. The Multifunctional Contribution of FGF Signaling to Cardiac Development, Homeostasis, Disease and Repair. Front Cell Dev Biol 2021; 9:672935. [PMID: 34095143 PMCID: PMC8169986 DOI: 10.3389/fcell.2021.672935] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 04/20/2021] [Indexed: 12/13/2022] Open
Abstract
The current focus on cardiovascular research reflects society’s concerns regarding the alarming incidence of cardiac-related diseases and mortality in the industrialized world and, notably, an urgent need to combat them by more efficient therapies. To pursue these therapeutic approaches, a comprehensive understanding of the mechanism of action for multifunctional fibroblast growth factor (FGF) signaling in the biology of the heart is a matter of high importance. The roles of FGFs in heart development range from outflow tract formation to the proliferation of cardiomyocytes and the formation of heart chambers. In the context of cardiac regeneration, FGFs 1, 2, 9, 16, 19, and 21 mediate adaptive responses including restoration of cardiac contracting rate after myocardial infarction and reduction of myocardial infarct size. However, cardiac complications in human diseases are correlated with pathogenic effects of FGF ligands and/or FGF signaling impairment. FGFs 2 and 23 are involved in maladaptive responses such as cardiac hypertrophic, fibrotic responses and heart failure. Among FGFs with known causative (FGFs 2, 21, and 23) or protective (FGFs 2, 15/19, 16, and 21) roles in cardiac diseases, FGFs 15/19, 21, and 23 display diagnostic potential. The effective role of FGFs on the induction of progenitor stem cells to cardiac cells during development has been employed to boost the limited capacity of postnatal cardiac repair. To renew or replenish damaged cardiomyocytes, FGFs 1, 2, 10, and 16 were tested in (induced-) pluripotent stem cell-based approaches and for stimulation of cell cycle re-entry in adult cardiomyocytes. This review will shed light on the wide range of beneficiary and detrimental actions mediated by FGF ligands and their receptors in the heart, which may open new therapeutic avenues for ameliorating cardiac complications.
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Affiliation(s)
- Farhad Khosravi
- Department of Physiology, Justus Liebig University Giessen, Giessen, Germany
| | - Negah Ahmadvand
- Cardio-Pulmonary Institute, Justus Liebig University Giessen, Giessen, Germany
| | - Saverio Bellusci
- Cardio-Pulmonary Institute, Justus Liebig University Giessen, Giessen, Germany
| | - Heinrich Sauer
- Department of Physiology, Justus Liebig University Giessen, Giessen, Germany
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16
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Regulatory role of endogenous and exogenous fibroblast growth factor 1 in the cardiovascular system and related diseases. Pharmacol Res 2021; 169:105596. [PMID: 33831565 DOI: 10.1016/j.phrs.2021.105596] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/29/2020] [Revised: 03/07/2021] [Accepted: 03/31/2021] [Indexed: 12/15/2022]
Abstract
Fibroblast growth factor 1 (FGF1) has a critical regulatory role in the development of the cardiovascular system (CVS) and is strongly associated with the progression or treatment of cardiovascular diseases (CVDs). However, the regulatory mechanisms of FGF1 in CVS and CVDs have not yet been fully elucidated. Therefore, this review article summarized the existing literature reports on the role of FGF1 in CVS under physiological and pathological conditions. First, the expression and physiological functions of endogenous FGF1 is fully demonstrated. Then, we analyzed the role of exogenous FGF1 in normal CVS and related pathological processes. Specifically, the potential signaling pathways might be mediated by FGF1 in CVDs treatment is discussed in detail. In addition, the barriers and feasible solutions for the application of FGF1 are further analyzed. Finally, we highlight therapeutic considerations of FGF1 for CVDs in the future. Thus, this article may be as a reference to provide some ideas for the follow-up research.
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FGF1 ΔHBS prevents diabetic cardiomyopathy by maintaining mitochondrial homeostasis and reducing oxidative stress via AMPK/Nur77 suppression. Signal Transduct Target Ther 2021; 6:133. [PMID: 33762571 PMCID: PMC7991671 DOI: 10.1038/s41392-021-00542-2] [Citation(s) in RCA: 65] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2020] [Revised: 03/07/2021] [Accepted: 03/08/2021] [Indexed: 02/01/2023] Open
Abstract
As a classically known mitogen, fibroblast growth factor 1 (FGF1) has been found to exert other pleiotropic functions such as metabolic regulation and myocardial protection. Here, we show that serum levels of FGF1 were decreased and positively correlated with fraction shortening in diabetic cardiomyopathy (DCM) patients, indicating that FGF1 is a potential therapeutic target for DCM. We found that treatment with a FGF1 variant (FGF1∆HBS) with reduced proliferative potency prevented diabetes-induced cardiac injury and remodeling and restored cardiac function. RNA-Seq results obtained from the cardiac tissues of db/db mice showed significant increase in the expression levels of anti-oxidative genes and decrease of Nur77 by FGF1∆HBS treatment. Both in vivo and in vitro studies indicate that FGF1∆HBS exerted these beneficial effects by markedly reducing mitochondrial fragmentation, reactive oxygen species (ROS) generation and cytochrome c leakage and enhancing mitochondrial respiration rate and β-oxidation in a 5' AMP-activated protein kinase (AMPK)/Nur77-dependent manner, all of which were not observed in the AMPK null mice. The favorable metabolic activity and reduced proliferative properties of FGF1∆HBS testify to its promising potential for use in the treatment of DCM and other metabolic disorders.
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Riching AS, Song K. Cardiac Regeneration: New Insights Into the Frontier of Ischemic Heart Failure Therapy. Front Bioeng Biotechnol 2021; 8:637538. [PMID: 33585427 PMCID: PMC7873479 DOI: 10.3389/fbioe.2020.637538] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Accepted: 12/29/2020] [Indexed: 12/17/2022] Open
Abstract
Ischemic heart disease is the leading cause of morbidity and mortality in the world. While pharmacological and surgical interventions developed in the late twentieth century drastically improved patient outcomes, mortality rates over the last two decades have begun to plateau. Following ischemic injury, pathological remodeling leads to cardiomyocyte loss and fibrosis leading to impaired heart function. Cardiomyocyte turnover rate in the adult heart is limited, and no clinical therapies currently exist to regenerate cardiomyocytes lost following ischemic injury. In this review, we summarize the progress of therapeutic strategies including revascularization and cell-based interventions to regenerate the heart: transiently inducing cardiomyocyte proliferation and direct reprogramming of fibroblasts into cardiomyocytes. Moreover, we highlight recent mechanistic insights governing these strategies to promote heart regeneration and identify current challenges in translating these approaches to human patients.
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Affiliation(s)
- Andrew S. Riching
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- The Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
| | - Kunhua Song
- Division of Cardiology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Gates Center for Regenerative Medicine and Stem Cell Biology, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- The Consortium for Fibrosis Research & Translation, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
- Pharmacology Graduate Program, University of Colorado Anschutz Medical Campus, Aurora, CO, United States
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Exosomes: Their Role in Pathogenesis, Diagnosis and Treatment of Diseases. Cancers (Basel) 2020; 13:cancers13010084. [PMID: 33396739 PMCID: PMC7795854 DOI: 10.3390/cancers13010084] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2020] [Revised: 12/18/2020] [Accepted: 12/24/2020] [Indexed: 02/07/2023] Open
Abstract
Simple Summary The aim of this review is to provide an overview of the current scientific evidence concerning the role played by exosomes in the pathogenesis, diagnosis and treatment of diseases. The potential use of exosomes as delivery vectors for small-molecule therapeutic agents will be discussed. In addition, a special emphasis will be placed on the involvement of exosomes in oncological diseases, as well as to their potential therapeutic application as liquid biopsy tools mainly in cancer diagnosis. A better understanding of exosome biology could improve the results of clinical interventions using exosomes as therapeutic agents. Abstract Exosomes are lipid bilayer particles released from cells into their surrounding environment. These vesicles are mediators of near and long-distance intercellular communication and affect various aspects of cell biology. In addition to their biological function, they play an increasingly important role both in diagnosis and as therapeutic agents. In this paper, we review recent literature related to the molecular composition of exosomes, paying special attention to their role in pathogenesis, along with their application as biomarkers and as therapeutic tools. In this context, we analyze the potential use of exosomes in biomedicine, as well as the limitations that preclude their wider application.
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20
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Yang Q, Fang J, Lei Z, Sluijter JPG, Schiffelers R. Repairing the heart: State-of the art delivery strategies for biological therapeutics. Adv Drug Deliv Rev 2020; 160:1-18. [PMID: 33039498 DOI: 10.1016/j.addr.2020.10.003] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2020] [Revised: 10/01/2020] [Accepted: 10/03/2020] [Indexed: 12/23/2022]
Abstract
Myocardial infarction (MI) is one of the leading causes of mortality worldwide. It is caused by an acute imbalance between oxygen supply and demand in the myocardium, usually caused by an obstruction in the coronary arteries. The conventional therapy is based on the application of (a combination of) anti-thrombotics, reperfusion strategies to open the occluded artery, stents and bypass surgery. However, numerous patients cannot fully recover after these interventions. In this context, new therapeutic methods are explored. Three decades ago, the first biologicals were tested to improve cardiac regeneration. Angiogenic proteins gained popularity as potential therapeutics. This is not straightforward as proteins are delicate molecules that in order to have a reasonably long time of activity need to be stabilized and released in a controlled fashion requiring advanced delivery systems. To ensure long-term expression, DNA vectors-encoding for therapeutic proteins have been developed. Here, the nuclear membrane proved to be a formidable barrier for efficient expression. Moreover, the development of delivery systems that can ensure entry in the target cell, and also correct intracellular trafficking towards the nucleus are essential. The recent introduction of mRNA as a therapeutic entity has provided an attractive intermediate: prolonged but transient expression from a cytoplasmic site of action. However, protection of the sensitive mRNA and correct delivery within the cell remains a challenge. This review focuses on the application of synthetic delivery systems that target the myocardium to stimulate cardiac repair using proteins, DNA or RNA.
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Affiliation(s)
- Qiangbing Yang
- Division LAB, CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Juntao Fang
- Division Heart & Lungs, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Zhiyong Lei
- Division LAB, CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands; Division Heart & Lungs, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands
| | - Joost P G Sluijter
- Division Heart & Lungs, Department of Cardiology, Experimental Cardiology Laboratory, University Medical Center Utrecht, Utrecht, the Netherlands; Regenerative Medicine Utrecht, Circulatory Health Laboratory, Utrecht University, Utrecht, the Netherlands
| | - Raymond Schiffelers
- Division LAB, CDL Research, University Medical Center Utrecht, Utrecht, the Netherlands.
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21
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Kang W, Cheng Y, Wang X, Zhou F, Zhou C, Wang L, Zhong L. Neuregulin‑1: An underlying protective force of cardiac dysfunction in sepsis (Review). Mol Med Rep 2020; 21:2311-2320. [PMID: 32236630 PMCID: PMC7185085 DOI: 10.3892/mmr.2020.11034] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2019] [Accepted: 03/04/2020] [Indexed: 11/10/2022] Open
Abstract
Neuregulin-1 (NRG-1) is a type of epidermal growth factor‑like protein primarily distributed in the nervous and cardiovascular systems. When sepsis occurs, the incidence of cardiac dysfunction in myocardial injury is high and the mechanism is complicated. It directly causes myocardial cell damage, whilst also causing damage to the structure and function of myocardial cells, weakening of endothelial function and coronary microcirculation, autonomic dysfunction, and activation of myocardial inhibitory factors. Studies investigating NRG‑1 have been performed using a variety of methods, including in vitro models, and animal and human clinical trials; however, the results are not consistent. NRG‑1/ErbBs signaling is involved in a variety of cardiac processes, from the development of the myocardium and cardiac conduction systems to the promotion of angiogenesis in cardiomyocytes, and in cardio‑protective effects during injury. NRG‑1 may exert a multifaceted cardiovascular protective effect by activating NRG‑1/ErbBs signaling and regulating multiple downstream signaling pathways, thereby improving myocardial cell dysfunction in sepsis, and protecting cardiomyocytes and endothelial cells. It may alleviate myocardial microvascular endothelial injury in sepsis; its anti‑inflammatory effects inhibit the production of myocardial inhibitory factors in sepsis, improve myocardial ischemia, decrease oxidative stress, regulate the disruption to the homeostasis of the autonomic nervous system, improve diastolic function, and offer protective effects at multiple target sites. As the mechanism of action of NRG‑1 intersects with the pathways involved in the pathogenesis of sepsis, it may be applicable as a treatment strategy to numerous pathological processes in sepsis.
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Affiliation(s)
- Wen Kang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Yue Cheng
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Fang Zhou
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Chenliang Zhou
- Department of Critical Care Medicine, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Long Wang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Liang Zhong
- Department of Anesthesiology, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei 430060, P.R. China
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22
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Garbayo E, Pascual‐Gil S, Rodríguez‐Nogales C, Saludas L, Estella‐Hermoso de Mendoza A, Blanco‐Prieto MJ. Nanomedicine and drug delivery systems in cancer and regenerative medicine. WILEY INTERDISCIPLINARY REVIEWS-NANOMEDICINE AND NANOBIOTECHNOLOGY 2020; 12:e1637. [DOI: 10.1002/wnan.1637] [Citation(s) in RCA: 36] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/07/2020] [Revised: 03/01/2020] [Accepted: 03/27/2020] [Indexed: 12/18/2022]
Affiliation(s)
- Elisa Garbayo
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition University of Navarra Pamplona Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA) Pamplona Spain
| | - Simon Pascual‐Gil
- Toronto General Hospital Research Institute, University Health Network Toronto Ontario Canada
- Institute of Biomaterials and Biomedical Engineering University of Toronto Toronto Ontario Canada
| | - Carlos Rodríguez‐Nogales
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition University of Navarra Pamplona Spain
| | - Laura Saludas
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition University of Navarra Pamplona Spain
| | | | - Maria J. Blanco‐Prieto
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition University of Navarra Pamplona Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA) Pamplona Spain
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Guan JT, Li XX, Peng DW, Zhang WM, Qu J, Lu F, D'Amato RJ, Chi ZL. MicroRNA-18a-5p Administration Suppresses Retinal Neovascularization by Targeting FGF1 and HIF1A. Front Pharmacol 2020; 11:276. [PMID: 32210827 PMCID: PMC7076186 DOI: 10.3389/fphar.2020.00276] [Citation(s) in RCA: 30] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/27/2019] [Accepted: 02/26/2020] [Indexed: 12/17/2022] Open
Abstract
Pathologic ocular neovascularization commonly results in visual impairment or even blindness in numerous fundus diseases, including proliferative diabetic retinopathy (PDR), retinopathy of prematurity (ROP), and age-related macular degeneration (AMD). MicroRNAs regulate angiogenesis through modulating target genes and disease progression, making them a new class of targets for drug discovery. In this study, we investigated the potential role of miR-18a-5p in retinal neovascularization using a mouse model of oxygen-induced proliferative retinopathy (OIR). We found that miR-18a-5p was highly expressed in the retina of pups as well as retinal endothelial cells, and was consistently down-regulated during retinal development. On the other hand, miR-18a-5p was increased significantly during pathologic neovascularization in the retinas of OIR mice. Moreover, intravitreal administration of miRNA mimic, agomiR-18a-5p, significantly suppressed retinal neovascularization in OIR models. Accordingly, agomir-18a-5p markedly suppressed human retinal microvascular endothelial cell (HRMEC) function including proliferation, migration, and tube formation ability. Additionally, we demonstrated that miR-18a-5p directly down-regulated known vascular growth factors, fibroblast growth factor 1 (FGF1) and hypoxia-inducible factor 1-alpha (HIF1A), as the target genes. In conclusion, miR-18a-5p may be a useful drug target for pathologic ocular neovascularization.
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Affiliation(s)
- Ji-Tian Guan
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Xin-Xin Li
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - De-Wei Peng
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Wen-Meng Zhang
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Jia Qu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China
| | - Fan Lu
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China.,International Joint Research Center for Regenerative Medicine and Neurogenetics, Wenzhou Medical University, Wenzhou, China
| | - Robert J D'Amato
- Vascular Biology Program, Department of Surgery, Boston Children's Hospital, Boston, MA, United States.,Department of Ophthalmology, Harvard Medical School, Boston, MA, United States
| | - Zai-Long Chi
- State Key Laboratory of Ophthalmology, Optometry and Visual Science, Eye Hospital of Wenzhou Medical University, Wenzhou, China.,International Joint Research Center for Regenerative Medicine and Neurogenetics, Wenzhou Medical University, Wenzhou, China
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Potential targets for intervention against doxorubicin-induced cardiotoxicity based on genetic studies: a systematic review of the literature. J Mol Cell Cardiol 2020; 138:88-98. [DOI: 10.1016/j.yjmcc.2019.11.150] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2019] [Revised: 10/24/2019] [Accepted: 11/03/2019] [Indexed: 12/12/2022]
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Quadros HC, Santos LDMF, Meira CS, Khouri MI, Mattei B, Soares MBP, de Castro-Borges W, Farias LP, Formiga FR. Development and in vitro characterization of polymeric nanoparticles containing recombinant adrenomedullin-2 intended for therapeutic angiogenesis. Int J Pharm 2019; 576:118997. [PMID: 31893542 DOI: 10.1016/j.ijpharm.2019.118997] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 12/18/2019] [Accepted: 12/23/2019] [Indexed: 12/18/2022]
Abstract
Cardiovascular diseases (CVD) are the leading cause of death worldwide. Growth factor therapy has emerged as novel therapeutic strategy under investigation for CVD. In this sense, adrenomedullin-2 (ADM-2) has been recently identified as a new angiogenic factor able to regulate the regional blood flow and cardiovascular function. However, the therapeutic value of ADM-2 is limited by its short biological half-life and low plasma stability. Poly (lactic-co-glycolic acid) (PLGA) micro- and nanoparticles have been investigated as growth factor delivery systems for cardiac repair. In this study, we aimed to develop PLGA nanoparticles containing ADM-2 intended for therapeutic angiogenesis. PLGA nanoparticles containing ADM-2 were prepared by a double emulsion modified method, resulting in 300 nm-sized stable particles with zeta potential around - 30 mV. Electron microscopy analysis by SEM and TEM revealed spherical particles with a smooth surface. High encapsulation efficiency was reached (ca.70%), as quantified by ELISA. ADM-2 associated to polymer nanoparticles was also determined by EDS elemental composition analysis, SDS-PAGE and LC-MS/MS for peptide identification. In vitro release assays showed the sustained release of ADM-2 from polymer nanoparticles for 21 days. Cell viability experiments were performed in J774 macrophages and H9c2 cardiomyocyte cells, about which PLGA nanoparticles loaded with ADM-2 did not cause toxicity in the range 0.01-1 mg/ml. Of note, encapsulated ADM-2 significantly induced cell proliferation in EA.hy926 endothelial cells, indicating the ADM-2 bioactivity was preserved after the encapsulation process. Collectively, these results demonstrate the feasibility of using PLGA nanoparticles as delivery systems for the angiogenic peptide ADM-2, which could represent a novel approach for therapeutic angiogenesis in CVD using growth factor therapy.
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Affiliation(s)
- Helenita Costa Quadros
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil
| | - Laís de Macêdo Ferreira Santos
- Laboratório de Imunopatologia Keizo Asami (LIKA), Universidade Federal de Pernambuco (UFPE), Av. Prof. Moraes Rego, Cidade Universitária, 52171-011 Recife/PE, Brazil
| | - Cássio Santana Meira
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil
| | - Mariana Ivo Khouri
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil
| | - Bruno Mattei
- Laboratório de Enzimologia e Proteômica, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto (UFOP), Campus Morro do Cruzeiro, s/n, 35400-000 Ouro Preto/MG, Brazil
| | - Milena Botelho Pereira Soares
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil
| | - William de Castro-Borges
- Laboratório de Enzimologia e Proteômica, Instituto de Ciências Exatas e Biológicas, Universidade Federal de Ouro Preto (UFOP), Campus Morro do Cruzeiro, s/n, 35400-000 Ouro Preto/MG, Brazil
| | - Leonardo Paiva Farias
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil
| | - Fabio Rocha Formiga
- Instituto Gonçalo Moniz, Fundação Oswaldo Cruz (Fiocruz), Rua Waldemar Falcão, 121, Candeal, 40296-710 Salvador/BA, Brazil; Programa de Pós-Graduação em Biologia Celular e Molecular Aplicada, Universidade de Pernambuco (UPE), Rua Arnóbio Marques, 310, Santo Amaro, 50100-130 Recife/PE, Brazil.
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26
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Vahdat S, Pahlavan S, Mahmoudi E, Barekat M, Ansari H, Bakhshandeh B, Aghdami N, Baharvand H. Expansion of Human Pluripotent Stem Cell-derived Early Cardiovascular Progenitor Cells by a Cocktail of Signaling Factors. Sci Rep 2019; 9:16006. [PMID: 31690816 PMCID: PMC6831601 DOI: 10.1038/s41598-019-52516-8] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 10/16/2019] [Indexed: 11/15/2022] Open
Abstract
Cardiovascular progenitor cells (CPCs) derived from human pluripotent stem cells (hPSCs) are proposed to be invaluable cell sources for experimental and clinical studies. This wide range of applications necessitates large-scale production of CPCs in an in vitro culture system, which enables both expansion and maintenance of these cells. In this study, we aimed to develop a defined and efficient culture medium that uses signaling factors for large-scale expansion of early CPCs, called cardiogenic mesodermal cells (CMCs), which were derived from hPSCs. Chemical screening resulted in a medium that contained a reproducible combination of three factors (A83-01, bFGF, and CHIR99021) that generated 1014 CMCs after 10 passages without the propensity for tumorigenicity. Expanded CMCs retained their gene expression pattern, chromosomal stability, and differentiation tendency through several passages and showed both the safety and possible cardio-protective potentials when transplanted into the infarcted rat myocardium. These CMCs were efficiently cryopreserved for an extended period of time. This culture medium could be used for both adherent and suspension culture conditions, for which the latter is required for large-scale CMC production. Taken together, hPSC-derived CMCs exhibited self-renewal capacity in our simple, reproducible, and defined medium. These cells might ultimately be potential, promising cell sources for cardiovascular studies.
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Affiliation(s)
- Sadaf Vahdat
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Sara Pahlavan
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Elena Mahmoudi
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Maryam Barekat
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hassan Ansari
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Behnaz Bakhshandeh
- Department of Biotechnology, College of Science, University of Tehran, Tehran, Iran
| | - Nasser Aghdami
- Department of Regenerative Medicine, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran
| | - Hossein Baharvand
- Department of Stem Cells and Developmental Biology, Cell Science Research Center, Royan Institute for Stem Cell Biology and Technology, ACECR, Tehran, Iran.
- Department of Developmental Biology, University of Science and Culture, Tehran, Iran.
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27
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Yuan QL, Zhang YG, Chen Q. Mesenchymal Stem Cell (MSC)-Derived Extracellular Vesicles: Potential Therapeutics as MSC Trophic Mediators in Regenerative Medicine. Anat Rec (Hoboken) 2019; 303:1735-1742. [PMID: 31168963 DOI: 10.1002/ar.24186] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2018] [Revised: 12/29/2018] [Accepted: 02/07/2019] [Indexed: 12/21/2022]
Abstract
Mesenchymal stem cells (MSCs) are pluripotent progenitor cells with the capabilities of self-renewing, differentiating into multiple lineages, and achieving trophic effects during tissue repair. MSCs can secrete extracellular vesicles (EVs) including exosomes and microvesicles, which mediate their trophic effects on other cells. Carrying a variety of intracellular molecules of MSCs including lipids, proteins, RNA (mRNA and noncoding RNA), and DNA, EVs deliver them into other cells to regulate tissue regeneration process. The therapeutic effects of MSC-derived EVs have been observed in a number of animal disease models. In this review, we focus on the current state and future directions of MSC-derived EVs in regenerative medicine. Anat Rec, 2019. © 2019 Wiley Periodicals, Inc.
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Affiliation(s)
- Qi-Ling Yuan
- Department of Orthopaedics, Bone and Joint Research Center, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Yin-Gang Zhang
- Department of Orthopaedics, Bone and Joint Research Center, The First Affiliated Hospital, Xi'an Jiaotong University, Xi'an, China
| | - Qian Chen
- Department of Orthopaedics, Brown University, Rhode Island Hospital, Providence, Rhode Island
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28
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Carlini AS, Gaetani R, Braden RL, Luo C, Christman KL, Gianneschi NC. Enzyme-responsive progelator cyclic peptides for minimally invasive delivery to the heart post-myocardial infarction. Nat Commun 2019; 10:1735. [PMID: 30988291 PMCID: PMC6465301 DOI: 10.1038/s41467-019-09587-y] [Citation(s) in RCA: 77] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2018] [Accepted: 03/11/2019] [Indexed: 01/08/2023] Open
Abstract
Injectable biopolymer hydrogels have gained attention for use as scaffolds to promote cardiac function and prevent negative left ventricular (LV) remodeling post-myocardial infarction (MI). However, most hydrogels tested in preclinical studies are not candidates for minimally invasive catheter delivery due to excess material viscosity, rapid gelation times, and/or concerns regarding hemocompatibility and potential for embolism. We describe a platform technology for progelator materials formulated as sterically constrained cyclic peptides which flow freely for low resistance injection, and rapidly assemble into hydrogels when linearized by disease-associated enzymes. Their utility in vivo is demonstrated by their ability to flow through a syringe and gel at the site of MI in rat models. Additionally, synthetic functionalization enables these materials to flow through a cardiac injection catheter without clogging, without compromising hemocompatibility or cytotoxicity. These studies set the stage for the development of structurally dynamic biomaterials for therapeutic hydrogel delivery to the MI.
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Affiliation(s)
- Andrea S Carlini
- Department of Chemistry & Biochemistry, University of California, San Diego, La Jolla, CA, 92093, USA
- Department of Chemistry, Department of Materials Science & Engineering, Department of Biomedical Engineering, Simpson Querrey Institute for BioNanotechnology, International Institute for Nanotechnology, and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA
| | - Roberto Gaetani
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Rebecca L Braden
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Colin Luo
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA
| | - Karen L Christman
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, CA, 92093, USA.
| | - Nathan C Gianneschi
- Department of Chemistry, Department of Materials Science & Engineering, Department of Biomedical Engineering, Simpson Querrey Institute for BioNanotechnology, International Institute for Nanotechnology, and Chemistry of Life Processes Institute, Northwestern University, Evanston, IL, 60208, USA.
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29
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Rao P, Liu Z, Duan H, Dang S, Li H, Zhong L, Wang X, Wang L, Wang X. Pretreatment with neuregulin-1 improves cardiac electrophysiological properties in a rat model of myocardial infarction. Exp Ther Med 2019; 17:3141-3149. [PMID: 30936986 PMCID: PMC6434250 DOI: 10.3892/etm.2019.7306] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2018] [Accepted: 02/01/2019] [Indexed: 12/22/2022] Open
Abstract
Neuregulin-1 (NRG-1) is considered to be a potential therapeutic agent for cardiovascular diseases due to its diverse protective effects. The aim of the present study was to investigate the effect of NRG-1 on cardiac electrophysiology in rats with myocardial infarction (MI). The rats were randomly divided into three groups: The sham operation group (SO; n=8); MI group (n=8); and the MI with recombinant human NRG (rhNRG)-1 administration group (NRG-1 group; 10 µg/kg; n=8). A rat MI model was established via ligation of the left anterior descending coronary artery. The rats in the NRG-1 group received a 10 µg/kg rhNRG-1 injection through the tail vein 30 min prior to ligation. Following 24 h of intervention, the field potential (FP) parameters, including the interspike interval (ISI), field potential duration (FPD), FPrise, FPmin, FPmax and conduction velocity (CV), were measured using microelectrode array technology. Subsequently, burst pacing was performed to assess ventricular arrhythmia (VA) susceptibility in the left ventricle. FP parameters in the MI group were significantly different when compared with those observed in the SO group. ISI, FPD, FPrise and FPmax in the infarct, peri-infarct and normal zones, as well as the CV of the infarct and peri-infarct zones, were all significantly decreased, and FPmin in the normal zone was increased (P<0.05). However, when compared with the MI group, NRG-1 prolonged the ISI and FPD in the 3 zones, and increased FPrise in the infarct zone, FPmax in the normal zone and CV in the peri-infarct zone; it also decreased FPmin in the normal zone (P<0.05). Furthermore, the incidence of VA was significantly reduced in the NRG-1 group when compared with the MI group (P<0.05). In conclusion, NRG-1 improved cardiac electrophysiological properties and reduced VA susceptibility in acute MI.
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Affiliation(s)
- Panpan Rao
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China
| | - Ziqiang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China
| | - Huinan Duan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Department of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China
| | - Song Dang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China
| | - Haitao Li
- Department of Cardiology, Hainan General Hospital, Haikou, Hainan 570100, P.R. China
| | - Liang Zhong
- Department of Anesthesiology, Wuhan Medical and Healthcare Center for Women and Children, Wuhan, Hubei 430015, P.R. China
| | - Xin Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China
| | - Long Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China.,Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China
| | - Xi Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, Hubei 430060, P.R. China.,Cardiovascular Research Institute, Wuhan University, Wuhan, Hubei 430060, P.R. China.,Hubei Key Laboratory of Cardiology, Wuhan Pulmonary Hospital, Wuhan, Hubei 430060, P.R. China
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30
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Remote ischemic perconditioning attenuates adverse cardiac remodeling and preserves left ventricular function in a rat model of reperfused myocardial infarction. Int J Cardiol 2019; 285:72-79. [PMID: 30904281 DOI: 10.1016/j.ijcard.2019.03.003] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Revised: 02/22/2019] [Accepted: 03/01/2019] [Indexed: 01/01/2023]
Abstract
AIMS Remote ischemic conditioning (RIC) is considered a potential clinical approach to reduce myocardial infarct size and ameliorate adverse post-infarct left ventricular (LV) remodeling, however the mechanisms are unknown. The aim was to clarify the impact of RIC on Neuregulin-1 (NRG-1)/ErbBs expression, inflammation and LV hemodynamic function. METHODS AND RESULTS Male Sprague-Dawley rats were subjected to 30 min occlusion of the left coronary artery (LCA) followed by 2 weeks of reperfusion and separated into three groups: (1) sham operated (without LCA occlusion); (2) Myocardial ischemia/reperfusion (MIR) and (3) remote ischemic perconditioning group (MIR + RIPerc). Cardiac structural and functional changes were evaluated by echocardiography and on the isolated working heart system. The level of H3K4me3 at the NRG-1 promoter, and both plasma and LV tissue levels of NRG-1 were assessed. The expression of pro-inflammatory cytokines, ECM components and ErbB receptors were assessed by RT-qPCR. MIR resulted in a significant decrease in LV function and enlargement of LV chamber. This was accompanied with a decrease in the level of H3K4me3 at the NRG-1 promoter. Consequently NRG-1 protein levels were reduced in the infarcted myocardium. Subsequently, an upregulated influx of CD68+ macrophages, high expression of MMP-2 and -9 as well as an increase of IL-1β, TLR-4, TNF-α, TNC expression were observed. In contrast, RIPerc significantly decreased inflammation and improved LV function in association with the enhancement of NRG-1 levels and ErbB3 expression. CONCLUSIONS These findings may reveal a novel anti-remodeling and anti-inflammatory effect of RIPerc, involving activation of NRG-1/ErbB3 signaling.
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31
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Wang X, Wang L, Wu Q, Bao F, Yang H, Qiu X, Chang J. Chitosan/Calcium Silicate Cardiac Patch Stimulates Cardiomyocyte Activity and Myocardial Performance after Infarction by Synergistic Effect of Bioactive Ions and Aligned Nanostructure. ACS APPLIED MATERIALS & INTERFACES 2019; 11:1449-1468. [PMID: 30543278 DOI: 10.1021/acsami.8b17754] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
Cardiac tissue engineering (CTE) remains a great challenge to construct a cell-inductive scaffold that has positive effects on cardiac cell behaviors and cardiac tissue repair. In this study, we for the first time demonstrated that Si ions evidently stimulated the expression of cardiac-specific genes and proliferation of neonatal rat cardiomyocytes (NRCMs) at concentration ranges of 0.13-10.78 ppm. Accordingly, the optimized concentrations of calcium silicate (CS) were incorporated into the controllable aligned chitosan electrospun nanofibers, constructing the composite cardiac patch scaffolds. These scaffolds showed synergistic effect of bioactive chemical and structural signals on both cardiomyocytes and endothelial cells with aligned cell morphology and enhanced viability and function characterized by upregulated expressions of cardiac and angiogenic specific markers, improved myofilament structure, and better Ca2+ transients of NRCMs as compared to the scaffolds free of CS component or with disordered structures. The in vivo studies further demonstrated that the NRCM-seeded aligned CS/chitosan cardiac patch evidently improved cardiac function via limiting the scar area and promoting angiogenesis in postmyocardial infarction rats. Conclusively, our study highlights the potential application of bioactive ions and nanostructured biomaterials in CTE, and the CS/chitosan composite cardiac patch may be a promising scaffold for repair of infarcted myocardium.
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Affiliation(s)
- Xiaotong Wang
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics , Chinese Academy of Sciences (CAS) , Shanghai 200050 , P. R. China
- University of Chinese Academy of Sciences (CAS) , Beijing 100049 , P. R. China
| | - Leyu Wang
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science, School of Biomedical Engineering , Southern Medical University , Guangzhou 510515 , Guangdong , P. R. China
| | - Qiang Wu
- CAS Key Laboratory of Tissue Microenvironment & Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health , Shanghai Institutes for Biological Sciences, CAS , Shanghai 200031 , P. R. China
- University of Chinese Academy of Sciences (CAS) , Beijing 100049 , P. R. China
- Institute for Stem Cell and Regeneration , Chinese Academy of Sciences (CAS) , Beijing 100101 , P. R. China
| | - Feng Bao
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics , Chinese Academy of Sciences (CAS) , Shanghai 200050 , P. R. China
- University of Chinese Academy of Sciences (CAS) , Beijing 100049 , P. R. China
| | - Huangtian Yang
- CAS Key Laboratory of Tissue Microenvironment & Tumor, Laboratory of Molecular Cardiology, Shanghai Institute of Nutrition and Health , Shanghai Institutes for Biological Sciences, CAS , Shanghai 200031 , P. R. China
- University of Chinese Academy of Sciences (CAS) , Beijing 100049 , P. R. China
- Institute for Stem Cell and Regeneration , Chinese Academy of Sciences (CAS) , Beijing 100101 , P. R. China
| | - Xiaozhong Qiu
- Guangdong Provincial Key Laboratory of Construction and Detection in Tissue Engineering, School of Basic Medical Science, School of Biomedical Engineering , Southern Medical University , Guangzhou 510515 , Guangdong , P. R. China
| | - Jiang Chang
- State Key Laboratory of High Performance Ceramics and Superfine Microstructure, Shanghai Institute of Ceramics , Chinese Academy of Sciences (CAS) , Shanghai 200050 , P. R. China
- University of Chinese Academy of Sciences (CAS) , Beijing 100049 , P. R. China
- Institute for Stem Cell and Regeneration , Chinese Academy of Sciences (CAS) , Beijing 100101 , P. R. China
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32
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Ding D, Zhu Q. Recent advances of PLGA micro/nanoparticles for the delivery of biomacromolecular therapeutics. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2018; 92:1041-1060. [DOI: 10.1016/j.msec.2017.12.036] [Citation(s) in RCA: 257] [Impact Index Per Article: 36.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 12/18/2017] [Accepted: 12/30/2017] [Indexed: 01/06/2023]
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33
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Pascual-Gil S, Abizanda G, Iglesias E, Garbayo E, Prósper F, Blanco-Prieto MJ. NRG1 PLGA MP locally induce macrophage polarisation toward a regenerative phenotype in the heart after acute myocardial infarction. J Drug Target 2018; 27:573-581. [DOI: 10.1080/1061186x.2018.1531417] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Affiliation(s)
- S. Pascual-Gil
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - G. Abizanda
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
| | - E. Iglesias
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
| | - E. Garbayo
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
| | - F. Prósper
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
- Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, Universidad de Navarra, Pamplona, Spain
| | - M. J. Blanco-Prieto
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, Spain
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, Spain
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34
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Huang S, Yang Y, Yang Q, Zhao Q, Ye X. Engineered circulatory scaffolds for building cardiac tissue. J Thorac Dis 2018; 10:S2312-S2328. [PMID: 30123572 DOI: 10.21037/jtd.2017.12.92] [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: 12/19/2022]
Abstract
Heart failure (HF) is the terminal state of cardiovascular disease (CVD), leading numerous patients to death every year. Cardiac tissue engineering is a multidisciplinary field of creating functional cardiac patches in vitro to promote cardiac function after transplantation onto damaged zone, giving the hope for patients with end-stage HF. However, the limited thickness of cardiac patches results in the graft failure of survival and function due to insufficient blood supply. To date, prevascularized cardiac tissue, with the use of circulatory scaffolds, holds the promise to be inosculated and perfused with host vasculature to eventually promote cardiac pumping function. Circulatory scaffolds play its role to provide oxygen and nutrients and take metabolic wastes away, and achieve anastomosis with host vasculature in vivo. Of worth note, heart-on-a-chip based on circulatory scaffolds now has been considered as a valuable unit to broaden the research for building cardiac tissue. In this review, we will present recent different strategies to engineer circulatory scaffolds for building cardiac tissue with microvasculature, followed by its current state and future direction.
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Affiliation(s)
- Shixing Huang
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Yang Yang
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Qi Yang
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Qiang Zhao
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Xiaofeng Ye
- Department of Cardiac Surgery, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
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35
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Deng H, Sun C, Sun Y, Li H, Yang L, Wu D, Gao Q, Jiang X. Lipid, Protein, and MicroRNA Composition Within Mesenchymal Stem Cell-Derived Exosomes. Cell Reprogram 2018; 20:178-186. [PMID: 29782191 DOI: 10.1089/cell.2017.0047] [Citation(s) in RCA: 92] [Impact Index Per Article: 13.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
Mesenchymal stem cells (MSCs) were regarded as one of the most promising type of seed cells in tissue engineering due to its easy accessibility and multipotent feature of being able to differentiate into adipocyte, osteoblast, cardiomyocytes, and neurons. For years, MSCs have been applied in treating cardiovascular disease, reconstructing kidney injury, and remodeling immune system with remarkable achievements. Basic researches revealed that its clinic effects are not only due to their pluripotent ability but also through their paracrine function that they synthesize and secrete a broad spectrum of growth factors and cytokines. Recent studies show that exosomes is the main paracrine executor of MSCs. The lipid bilayer of exosome maintains its stability and integrity and keeps biological potency of biological substance within it. MSC-derived exosomes were shown to be successful in treating many diseases, including tumor and cardiovascular diseases. However, the exact composition of MSC-derived exosomes is not known yet. In this review, we will discuss the lipid, protein, and microRNA contents within MSC-derived exosomes based on current studies to guide further research and clinical applications of MSC-derived exosomes.
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Affiliation(s)
- Hao Deng
- 1 First Teaching Hospital of Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Chun Sun
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Yingxin Sun
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Huhu Li
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Lin Yang
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Danbin Wu
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Qing Gao
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
| | - Xijuan Jiang
- 2 School of Integrative Medicine, Tianjin University of Traditional Chinese Medicine , Tianjin, China
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36
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Saludas L, Pascual-Gil S, Roli F, Garbayo E, Blanco-Prieto MJ. Heart tissue repair and cardioprotection using drug delivery systems. Maturitas 2018; 110:1-9. [DOI: 10.1016/j.maturitas.2018.01.011] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 12/26/2017] [Accepted: 01/12/2018] [Indexed: 12/23/2022]
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37
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Rask-Andersen M, Martinsson D, Ahsan M, Enroth S, Ek WE, Gyllensten U, Johansson Å. Epigenome-wide association study reveals differential DNA methylation in individuals with a history of myocardial infarction. Hum Mol Genet 2018; 25:4739-4748. [PMID: 28172975 DOI: 10.1093/hmg/ddw302] [Citation(s) in RCA: 50] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2016] [Revised: 08/24/2016] [Accepted: 08/26/2016] [Indexed: 12/24/2022] Open
Abstract
Cardiovascular diseases (CVDs) are the leading causes of death worldwide and represent a substantial economic burden on public health care systems. Epigenetic markers have potential as diagnostic markers before clinical symptoms have emerged, and as prognostic markers to inform the choice of clinical intervention. In this study, we performed an epigenome-wide association study (EWAS) for CVDs, to identify disease-specific alterations in DNA methylation. CpG methylation in blood samples from the northern Sweden population health study (NSPHS) (n = 729) was assayed on the Illumina Infinium HumanMethylation450 BeadChip. Individuals with a history of a CVD were identified in the cohort. It included individuals with hypertension (N = 147), myocardial infarction (MI) (N = 48), stroke (N = 27), thrombosis (N = 22) and cardiac arrhythmia (N = 5). Differential DNA methylation was observed at 211 CpG-sites in individuals with a history of MI (q <0.05). These sites represent 196 genes, of which 42 have been described in the scientific literature to be related to cardiac function, cardiovascular disease, cardiogenesis and recovery after ischemic injury. We have shown that individuals with a history of MI have a deviating pattern of DNA methylation at many genomic loci of which a large fraction has previously been linked to CVD. Our results highlight genes that might be important in the pathogenesis of MI or in recovery. In addition, the sites pointed out in this study can serve as candidates for further evaluation as potential biomarkers for MI.
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Affiliation(s)
- Mathias Rask-Andersen
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - David Martinsson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Muhammad Ahsan
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Stefan Enroth
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Weronica E Ek
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Ulf Gyllensten
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
| | - Åsa Johansson
- Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden
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38
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Martins JP, Ferreira MP, Ezazi NZ, Hirvonen JT, Santos HA, Thrivikraman G, França CM, Athirasala A, Tahayeri A, Bertassoni LE. 3D printing: prospects and challenges. NANOTECHNOLOGIES IN PREVENTIVE AND REGENERATIVE MEDICINE 2018:299-379. [DOI: 10.1016/b978-0-323-48063-5.00004-6] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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39
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Toischer K, Zhu W, Hünlich M, Mohamed BA, Khadjeh S, Reuter SP, Schäfer K, Ramanujam D, Engelhardt S, Field LJ, Hasenfuss G. Cardiomyocyte proliferation prevents failure in pressure overload but not volume overload. J Clin Invest 2017; 127:4285-4296. [PMID: 29083322 DOI: 10.1172/jci81870] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2015] [Accepted: 09/26/2017] [Indexed: 12/17/2022] Open
Abstract
Induction of the cell cycle is emerging as an intervention to treat heart failure. Here, we tested the hypothesis that enhanced cardiomyocyte renewal in transgenic mice expressing cyclin D2 would be beneficial during hemodynamic overload. We induced pressure overload by transthoracic aortic constriction (TAC) or volume overload by aortocaval shunt in cyclin D2-expressing and WT mice. Although cyclin D2 expression dramatically improved survival following TAC, it did not confer a survival advantage to mice following aortocaval shunt. Cardiac function decreased following TAC in WT mice, but was preserved in cyclin D2-expressing mice. On the other hand, cardiac structure and function were compromised in response to aortocaval shunt in both WT and cyclin D2-expressing mice. The preserved function and improved survival in cyclin D2-expressing mice after TAC was associated with an approximately 50% increase in cardiomyocyte number and exaggerated cardiac hypertrophy, as indicated by increased septum thickness. Aortocaval shunt did not further impact cardiomyocyte number in mice expressing cyclin D2. Following TAC, cyclin D2 expression attenuated cardiomyocyte hypertrophy, reduced cardiomyocyte apoptosis, fibrosis, calcium/calmodulin-dependent protein kinase IIδ phosphorylation, brain natriuretic peptide expression, and sustained capillarization. Thus, we show that cyclin D2-induced cardiomyocyte renewal reduced myocardial remodeling and dysfunction after pressure overload but not after volume overload.
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Affiliation(s)
- Karl Toischer
- Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Goettingen, Germany.,DZHK (German Center for Cardiovascular Research), partner site Goettingen, Goettingen, Germany
| | - Wuqiang Zhu
- Krannert Institute of Cardiology and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Mark Hünlich
- Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Goettingen, Germany
| | - Belal A Mohamed
- Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Goettingen, Germany.,Department of Medical Biochemistry and Molecular Biology, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| | - Sara Khadjeh
- Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Goettingen, Germany
| | - Sean P Reuter
- Krannert Institute of Cardiology and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Katrin Schäfer
- Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Goettingen, Germany.,Center for Cardiology, Cardiology I, University Medical Center Mainz, Mainz, Germany
| | - Deepak Ramanujam
- Institute of Pharmacology and Toxicology, Technical University of Munich, Munich, Germany.,DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Stefan Engelhardt
- Institute of Pharmacology and Toxicology, Technical University of Munich, Munich, Germany.,DZHK (German Center for Cardiovascular Research), partner site Munich Heart Alliance, Munich, Germany
| | - Loren J Field
- Krannert Institute of Cardiology and Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Gerd Hasenfuss
- Department of Cardiology and Pneumology, Heart Center, Georg-August-University, Goettingen, Germany.,DZHK (German Center for Cardiovascular Research), partner site Goettingen, Goettingen, Germany
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40
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Guo M, Shi JH, Wang PL, Shi DZ. Angiogenic Growth Factors for Coronary Artery Disease: Current Status and Prospects. J Cardiovasc Pharmacol Ther 2017; 23:130-141. [PMID: 29025278 DOI: 10.1177/1074248417735399] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Affiliation(s)
- Ming Guo
- China Heart Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jun-He Shi
- Department of Periodontics, University of Illinois at Chicago, Chicago, IL, USA
| | - Pei-Li Wang
- China Heart Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - Da-Zhuo Shi
- China Heart Institute of Chinese Medicine, China Academy of Chinese Medical Sciences, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
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41
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Huo M, Wang Z, Wu D, Zhang Y, Qiao Y. Using Coexpression Protein Interaction Network Analysis to Identify Mechanisms of Danshensu Affecting Patients with Coronary Heart Disease. Int J Mol Sci 2017. [PMID: 28629174 PMCID: PMC5486119 DOI: 10.3390/ijms18061298] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Salvia miltiorrhiza, known as Danshen, has attracted worldwide interest for its substantial effects on coronary heart disease (CHD). Danshensu (DSS) is one of the main active ingredients of Danshen on CHD. Although it has been proven to have a good clinical effect on CHD, the action mechanisms remain elusive. In the current study, a coexpression network-based approach was used to illustrate the beneficial properties of DSS in the context of CHD. By integrating the gene expression profile data and protein-protein interactions (PPIs) data, two coexpression protein interaction networks (CePIN) in a CHD state (CHD CePIN) and a non-CHD state (non-CHD CePIN) were generated. Then, shared nodes and unique nodes in CHD CePIN were attained by conducting a comparison between CHD CePIN and non-CHD CePIN. By calculating the topological parameters of each shared node and unique node in the networks, and comparing the differentially expressed genes, target proteins involved in disease regulation were attained. Then, Gene Ontology (GO) enrichment was utilized to identify biological processes associated to target proteins. Consequently, it turned out that the treatment of CHD with DSS may be partly attributed to the regulation of immunization and blood circulation. Also, it indicated that sodium/hydrogen exchanger 3 (SLC9A3), Prostaglandin G/H synthase 2 (PTGS2), Oxidized low-density lipoprotein receptor 1 (OLR1), and fibrinogen gamma chain (FGG) may be potential therapeutic targets for CHD. In summary, this study provided a novel coexpression protein interaction network approach to provide an explanation of the mechanisms of DSS on CHD and identify key proteins which maybe the potential therapeutic targets for CHD.
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Affiliation(s)
- Mengqi Huo
- Key Laboratory of Traditional Chinese Medicine Information Engineer of State Administration of Traditional Chinese Medicine; School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
| | - Zhixin Wang
- Key Laboratory of Traditional Chinese Medicine Information Engineer of State Administration of Traditional Chinese Medicine; School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
| | - Dongxue Wu
- Key Laboratory of Traditional Chinese Medicine Information Engineer of State Administration of Traditional Chinese Medicine; School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
| | - Yanling Zhang
- Key Laboratory of Traditional Chinese Medicine Information Engineer of State Administration of Traditional Chinese Medicine; School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
| | - Yanjiang Qiao
- Key Laboratory of Traditional Chinese Medicine Information Engineer of State Administration of Traditional Chinese Medicine; School of Chinese Material Medica, Beijing University of Chinese Medicine, Beijing 100102, China.
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42
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Hoseini SJ, Ghazavi H, Forouzanfar F, Mashkani B, Ghorbani A, Mahdipour E, Ghasemi F, Sadeghnia HR, Ghayour-Mobarhan M. Fibroblast Growth Factor 1-Transfected Adipose-Derived Mesenchymal Stem Cells Promote Angiogenic Proliferation. DNA Cell Biol 2017; 36:401-412. [PMID: 28281780 PMCID: PMC5421621 DOI: 10.1089/dna.2016.3546] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2016] [Revised: 01/28/2017] [Accepted: 02/08/2017] [Indexed: 01/10/2023] Open
Abstract
The aim of this study was to investigate, for the first time, the effects of using adipose-derived mesenchymal stem cells (AD-MSCs) transfected with an episomal plasmid encoding fibroblast growth factor 1 (FGF1) (AD-MSCsFGF1), in providing the microenvironment required for angiogenic proliferation. The isolated rat AD-MSCs were positive for mesenchymal (CD29 and CD90) and negative for hematopoietic (CD34 and CD45) surface markers. Adipogenic and osteogenic differentiation of the AD-MSCs also occurred in the proper culture media. The presence of FGF1 in the conditioned medium from the AD-MSCsFGF1 was confirmed by Western blotting. G418 and PCR were used for selection of transfected cells and confirmation of the presence of FGF1 mRNA, respectively. Treatment with the AD-MSCFGF1-conditioned medium significantly increased the NIH-3T3 cell proliferation and human umbilical vein endothelial cell (HUVEC) tube formation compared to conditioned medium from nontransfected AD-MSCs (p < 0.001). In conclusion, the AD-MSCsFGF1 efficiently secreted functional FGF1, which promoted angiogenic proliferation. Using AD-MSCsFGF1 may provide a useful strategy in cell therapy, which can merge the beneficial effects of stem cells with the positive biological effects of FGF1 in various disorders, especially tissue defects, neurodegenerative, cardiovascular and diabetes endocrine pathologies, which remain to be tested in preclinical and clinical studies.
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Affiliation(s)
- Seyed Javad Hoseini
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Ghazavi
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fatemeh Forouzanfar
- Department of Pharmacology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Baratali Mashkani
- Department of Biochemistry, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Ahmad Ghorbani
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Elahe Mahdipour
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Faezeh Ghasemi
- Department of Medical Biotechnology, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Reza Sadeghnia
- Neurocognitive Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Cardiovascular Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
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43
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Hydrogel based approaches for cardiac tissue engineering. Int J Pharm 2017; 523:454-475. [DOI: 10.1016/j.ijpharm.2016.10.061] [Citation(s) in RCA: 103] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 10/24/2016] [Accepted: 10/26/2016] [Indexed: 01/04/2023]
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44
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Xu HL, Yu WZ, Lu CT, Li XK, Zhao YZ. Delivery of growth factor-based therapeutics in vascular diseases: Challenges and strategies. Biotechnol J 2017; 12. [PMID: 28296342 DOI: 10.1002/biot.201600243] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2016] [Revised: 01/27/2017] [Accepted: 02/09/2017] [Indexed: 12/18/2022]
Abstract
Either cardiovascular or peripheral vascular diseases have become the major cause of morbidity and mortality worldwide. Recently, growth factors therapeutics, whatever administrated in form of exogenous growth factors or their relevant genes have been discovered to be an effective strategy for the prevention and therapy of vascular diseases, because of their promoting angiogenesis. Besides, as an alternative, stem cell-based therapy has been also developed in view of their paracrine-mediated effect or ability of differentiation toward angiogenesis-related cells under assistance of growth factors. Despite of being specific and potent, no matter growth factors or stem cells-based therapy, their full clinical transformation is limited from bench to bedside. In this review, the potential choices of therapeutic modes based on types of different growth factors or stem cells were firstly summarized for vascular diseases. The confronted various challenges such as lack of non-invasive delivery method, the physiochemical challenge, the short half-life time, and poor cell survival, were carefully analyzed for these therapeutic modes. Various strategies to overcome these limitations are put forward from the perspective of drug delivery. The expertised design of a suitable delivery form will undoubtedly provide valuable insight into their clinical application in the regenerative medicine.
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Affiliation(s)
- He-Lin Xu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Wen-Ze Yu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Cui-Tao Lu
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Xiao-Kun Li
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
- Collaborative Innovation Center of Biomedical Science by Wenzhou University & Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
| | - Ying-Zheng Zhao
- School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province, China
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45
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Hernandez MJ, Christman KL. Designing Acellular Injectable Biomaterial Therapeutics for Treating Myocardial Infarction and Peripheral Artery Disease. JACC Basic Transl Sci 2017; 2:212-226. [PMID: 29057375 PMCID: PMC5646282 DOI: 10.1016/j.jacbts.2016.11.008] [Citation(s) in RCA: 42] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2016] [Revised: 11/22/2016] [Accepted: 11/23/2016] [Indexed: 02/07/2023]
Abstract
As the number of global deaths attributed to cardiovascular disease continues to rise, viable treatments for cardiovascular events such as myocardial infarction (MI) or conditions like peripheral artery disease (PAD) are critical. Recent studies investigating injectable biomaterials have shown promise in promoting tissue regeneration and functional improvement, and in some cases, incorporating other therapeutics further augments the beneficial effects of these biomaterials. In this review, we aim to emphasize the advantages of acellular injectable biomaterial-based therapies, specifically material-alone approaches or delivery of acellular biologics, in regards to manufacturability and the capacity of these biomaterials to regenerate or repair diseased tissue. We will focus on design parameters and mechanisms that maximize therapeutic efficacy, particularly, improved functional perfusion and neovascularization regarding PAD and improved cardiac function and reduced negative left ventricular (LV) remodeling post-MI. We will then discuss the rationale and challenges of designing new injectable biomaterial-based therapies for the clinic.
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Affiliation(s)
| | - Karen L. Christman
- Department of Bioengineering, Sanford Consortium for Regenerative Medicine, University of California San Diego, La Jolla, California
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46
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Transplantation of adipose-derived stem cells combined with neuregulin-microparticles promotes efficient cardiac repair in a rat myocardial infarction model. J Control Release 2017; 249:23-31. [DOI: 10.1016/j.jconrel.2017.01.026] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2016] [Revised: 01/11/2017] [Accepted: 01/18/2017] [Indexed: 12/22/2022]
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47
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Suarez S, Almutairi A, Christman KL. Micro- and Nanoparticles for Treating Cardiovascular Disease. Biomater Sci 2016; 3:564-80. [PMID: 26146548 DOI: 10.1039/c4bm00441h] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022]
Abstract
Cardiovascular disease, including myocardial infarction (MI) and peripheral artery disease (PAD), afflicts millions of people in Unites States. Current therapies are insufficient to restore blood flow and repair the injured heart or skeletal muscle, respectively, which is subjected to ischemic damage following vessel occlusion. Micro- and nano-particles are being designed as delivery vehicles for growth factors, enzymes and/or small molecules to provide a sustained therapeutic stimulus at the injured tissue. Depending on the formulation, the particles can be injected directly into the heart or skeletal muscle, or accumulate at the site of injury following an intravenous injection. In this article we review existing particle based therapies for treating MI and PAD.
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Affiliation(s)
- S Suarez
- Department of Bioengineering and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, United States
| | - A Almutairi
- Skaggs School of Pharmacy and Pharmaceutical Sciences and KACST UCSD Center of Excellence in Nanomedicine, University of California, San Diego, La Jolla, California, United States
| | - K L Christman
- Department of Bioengineering and Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, United States
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48
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Abstract
In this review, we focus on new approaches that could lead to the regeneration of heart muscle and the restoration of cardiac muscle function derived from newly-formed cardiomyocytes. Various strategies for the production of cardiomyocytes from embryonic stem cells, induced pluripotent stem cells, adult bone marrow stem cells and cardiac spheres from human heart biopsies are described. Pathological conditions which lead to atherosclerosis and coronary artery disease often are followed by myocardial infarction causing myocardial cell death. After cell death, there is very little self-regeneration of the cardiac muscle tissue, which is replaced by non-contractile connective tissue, thus weakening the ability of the heart muscle to contract fully and leading to heart failure. A number of experimental research approaches to stimulate heart muscle regeneration with the hope of regaining normal or near normal heart function in the damaged heart muscle have been attempted. Some of these very interesting studies have used a variety of stem cell types in combination with potential cardiogenic differentiation factors in an attempt to promote differentiation of new cardiac muscle for possible future use in the clinical treatment of patients who have suffered heart muscle damage from acute myocardial infarctions or related cardiovascular diseases. Although progress has been made in recent years relative to promoting the differentiation of cardiac muscle tissue from non-muscle cells, much work remains to be done for this technology to be used routinely in translational clinical medicine to treat patients with damaged heart muscle tissue and return such individuals to pre-heart-attack activity levels.
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Affiliation(s)
- Andrei Kochegarov
- Department of Biological and Environmental Sciences, Texas A&M University-Commerce, Commerce, Texas, USA
| | - Larry F Lemanski
- Department of Biological and Environmental Sciences, Texas A&M University-Commerce, Commerce, Texas, USA
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49
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Samsa LA, Ito CE, Brown DR, Qian L, Liu J. IgG-Containing Isoforms of Neuregulin-1 Are Dispensable for Cardiac Trabeculation in Zebrafish. PLoS One 2016; 11:e0166734. [PMID: 27846271 PMCID: PMC5112773 DOI: 10.1371/journal.pone.0166734] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2016] [Accepted: 11/02/2016] [Indexed: 12/25/2022] Open
Abstract
The Neuregulin-1 (Nrg1) signaling pathway has been widely implicated in many aspects of heart development including cardiac trabeculation. Cardiac trabeculation is an important morphogenetic process where clusters of ventricular cardiomyocytes extrude and expand into the lumen of the ventricular chambers. In mouse, Nrg1 isoforms containing an immunoglobulin-like (IgG) domain are essential for cardiac trabeculation through interaction with heterodimers of the epidermal growth factor-like (EGF-like) receptors ErbB2/ErbB4. Recent reports have underscored the importance of Nrg1 signaling in cardiac homeostasis and disease, however, placental development has precluded refined evaluation of the role of this pathway in mammals. ErbB2 has been shown to have a developmentally conserved role in cardiac trabeculation in zebrafish, a vertebrate model organism with completely external development, but the requirement for Nrg1 has not been examined. We found that among the multiple Nrg1 isoforms, the IgG domain-containing, type I Nrg1 (nrg1-I) is the only isoform detectable in the heart. Then, using CRISPR/Cas9 gene editing, we targeted the IgG domain of Nrg1 to produce novel alleles, nrg1nc28 and nrg1nc29, encoding nrg1-I and nrg1-II truncations. Our results indicated that zebrafish deficient for nrg1-I developed trabeculae in an ErbB2-dependent manner. Further, these mutants survive to reproductive adulthood with no overt cardiovascular defects. We also found that additional EGF-like ligands were expressed in the zebrafish heart during development of trabeculae. Together, these results suggest that Nrg1 is not the primary effector of trabeculation and/or that other EGF-like ligand(s) activates the ErbB2/ErbB4 pathway, either through functioning as the primary ligand or acting in a redundant manner. Overall, our work provides an example of cross-species differences in EGF family member requirements for an evolutionary conserved process.
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Affiliation(s)
- Leigh Ann Samsa
- Department of Cell Biology and Physiology, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.,McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Cade Ellis Ito
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Daniel Ross Brown
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Li Qian
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
| | - Jiandong Liu
- McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America.,Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, United States of America
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50
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Pascual-Gil S, Simón-Yarza T, Garbayo E, Prósper F, Blanco-Prieto MJ. Cytokine-loaded PLGA and PEG-PLGA microparticles showed similar heart regeneration in a rat myocardial infarction model. Int J Pharm 2016; 523:531-533. [PMID: 27838293 DOI: 10.1016/j.ijpharm.2016.11.022] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2016] [Revised: 10/11/2016] [Accepted: 11/08/2016] [Indexed: 11/16/2022]
Abstract
Neuregulin (NRG1) and fibroblast growth factor (FGF1) are well known growth factors implicated in cardiomyocyte proliferation and survival, as well as in angiogenesis, the development of adult heart and the maintenance of cardiac function. NRG1 and FGF1 have become promising therapeutic agents to treat myocardial infarction (MI) disorder. Unfortunately, clinical trials performed so far reported negative efficacy results, because growth factors are rapidly degraded and eliminated from the biological tissues once administered. In order to increase their bioavailability and favour their therapeutic effects, they have been combined with poly(lactic-co-glycolic acid) and polyethylene glycol microparticles (PLGA MPs and PEG-PLGA MPs). Here we compare both types of microparticles loaded with NRG1 or FGF1 in terms of efficacy in a rat MI model. Our results showed that intramyocardial injection of NRG1 or FGF1-loaded PLGA and PEG-PLGA MPs brought about similar improvements in the ejection fraction, angiogenesis and arteriogenesis after administration into the infarcted hearts. PEG coating did not add any effect regarding MP efficacy. Both PLGA and PEG-PLGA MPs were equally phagocyted in the heart. To our knowledge, this is the first study analysing the opsonisation process in heart tissue. The results allow us to conclude that the opsonisation process is different in heart tissue compared to blood.
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Affiliation(s)
- Simon Pascual-Gil
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, C/Irunlarrea 1, E-31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, C/Irunlarrea 3, E-31008 Pamplona, Spain
| | - Teresa Simón-Yarza
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, C/Irunlarrea 1, E-31080, Spain
| | - Elisa Garbayo
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, C/Irunlarrea 1, E-31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, C/Irunlarrea 3, E-31008 Pamplona, Spain
| | - Felipe Prósper
- Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, C/Irunlarrea 3, E-31008 Pamplona, Spain; Hematology Service and Area of Cell Therapy, Clínica Universidad de Navarra, Foundation for Applied Medical Research, Universidad de Navarra, Pamplona, C/Irunlarrea 1, E-31080, Spain
| | - María J Blanco-Prieto
- Pharmacy and Pharmaceutical Technology Department, School of Pharmacy, Universidad de Navarra, Pamplona, C/Irunlarrea 1, E-31080, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, Pamplona, C/Irunlarrea 3, E-31008 Pamplona, Spain.
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