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1
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Hu Y, Zhang W, Ali SR, Takeda K, Vahl TP, Zhu D, Hong Y, Cheng K. Extracellular vesicle therapeutics for cardiac repair. J Mol Cell Cardiol 2025; 199:12-32. [PMID: 39603560 PMCID: PMC11788051 DOI: 10.1016/j.yjmcc.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 10/30/2024] [Accepted: 11/21/2024] [Indexed: 11/29/2024]
Abstract
Extracellular vesicles (EVs) are cell-secreted heterogeneous vesicles that play crucial roles in intercellular communication and disease pathogenesis. Due to their non-tumorigenicity, low immunogenicity, and therapeutic potential, EVs are increasingly used in cardiac repair as cell-free therapy. There exist multiple steps for the design of EV therapies, and each step offers many choices to tune EV properties. Factors such as EV source, cargo, loading methods, routes of administration, surface modification, and biomaterials are comprehensively considered to achieve specific goals. PubMed and Google Scholar were searched in this review, 89 articles related to EV-based cardiac therapy over the past five years (2019 Jan - 2023 Dec) were included, and their key steps in designing EV therapies were counted and analyzed. We aim to provide a comprehensive overview that can serve as a reference guide for researchers to design EV-based cardiac therapies.
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Affiliation(s)
- Yilan Hu
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Weihang Zhang
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA
| | - Shah Rukh Ali
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Koji Takeda
- Division of Cardiac Surgery, Department of Surgery, Columbia University, New York, NY 10032, USA
| | - Torsten Peter Vahl
- Division of Cardiology, Department of Medicine, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Donghui Zhu
- Department of Biomedical Engineering, College of Engineering and Applied Sciences, Stony Brook University, Stony Brook, NY 11794, USA
| | - Yi Hong
- Department of Bioengineering, University of Texas at Arlington, Arlington, TX 76019, USA
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York, NY 10032, USA.
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2
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He S, Yan L, Yuan C, Li W, Wu T, Chen S, Li N, Wu M, Jiang J. The role of cardiomyocyte senescence in cardiovascular diseases: A molecular biology update. Eur J Pharmacol 2024; 983:176961. [PMID: 39209099 DOI: 10.1016/j.ejphar.2024.176961] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Revised: 08/18/2024] [Accepted: 08/27/2024] [Indexed: 09/04/2024]
Abstract
Cardiovascular diseases (CVD) are the leading cause of death worldwide, and advanced age is a main contributor to the prevalence of CVD. Cellular senescence is an irreversible state of cell cycle arrest that occurs in old age or after cells encounter various stresses. Senescent cells not only result in the reduction of cellular function, but also produce senescence-associated secretory phenotype (SASP) to affect surrounding cells and tissue microenvironment. There is increasing evidence that the gradual accumulation of senescent cardiomyocytes is causally involved in the decline of cardiovascular system function. To highlight the role of senescent cardiomyocytes in the pathophysiology of age-related CVD, we first introduced that senescent cardiomyoyctes can be identified by structural changes and several senescence-associated biomarkers. We subsequently provided a comprehensive summary of existing knowledge, outlining the compelling evidence on the relationship between senescent cardiomyocytes and age-related CVD phenotypes. In addition, we discussed that the significant therapeutic potential represented by the prevention of accelerated senescent cardiomyocytes, and the current status of some existing geroprotectors in the prevention and treatment of age-related CVD. Together, the review summarized the role of cardiomyocyte senescence in CVD, and explored the molecular knowledge of senescent cardiomyocytes and their potential clinical significance in developing senescent-based therapies, thereby providing important insights into their biology and potential therapeutic exploration.
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Affiliation(s)
- Shuangyi He
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Li Yan
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China; Department of Pharmacy, Wuhan Asia General Hospital, Wuhan, 430056, China
| | - Chao Yuan
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Wenxuan Li
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Tian Wu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Suya Chen
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China
| | - Niansheng Li
- Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410078, China
| | - Meiting Wu
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China; Department of Nephrology, Institute of Nephrology, 2nd Affiliated Hospital of Hainan Medical University, Haikou, 570100, China
| | - Junlin Jiang
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan, 410078, China; Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, 410078, China.
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3
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Li H, Zhang J, Tan M, Yin Y, Song Y, Zhao Y, Yan L, Li N, Zhang X, Bai J, Jiang T, Li H. Exosomes based strategies for cardiovascular diseases: Opportunities and challenges. Biomaterials 2024; 308:122544. [PMID: 38579591 DOI: 10.1016/j.biomaterials.2024.122544] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2023] [Revised: 03/11/2024] [Accepted: 03/19/2024] [Indexed: 04/07/2024]
Abstract
Exosomes, as nanoscale extracellular vesicles (EVs), are secreted by all types of cells to facilitate intercellular communication in living organisms. After being taken up by neighboring or distant cells, exosomes can alter the expression levels of target genes in recipient cells and thereby affect their pathophysiological outcomes depending on payloads encapsulated therein. The functions and mechanisms of exosomes in cardiovascular diseases have attracted much attention in recent years and are thought to have cardioprotective and regenerative potential. This review summarizes the biogenesis and molecular contents of exosomes and details the roles played by exosomes released from various cells in the progression and recovery of cardiovascular disease. The review also discusses the current status of traditional exosomes in cardiovascular tissue engineering and regenerative medicine, pointing out several limitations in their application. It emphasizes that some of the existing emerging industrial or bioengineering technologies are promising to compensate for these shortcomings, and the combined application of exosomes and biomaterials provides an opportunity for mutual enhancement of their performance. The integration of exosome-based cell-free diagnostic and therapeutic options will contribute to the further development of cardiovascular regenerative medicine.
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Affiliation(s)
- Hang Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Jun Zhang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Mingyue Tan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China; Department of Geriatrics, Cardiovascular Center, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing, 400038, PR China
| | - Yunfei Yin
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Yiyi Song
- Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215000, PR China
| | - Yongjian Zhao
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Lin Yan
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China
| | - Ning Li
- Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230022, PR China
| | - Xianzuo Zhang
- Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230022, PR China
| | - Jiaxiang Bai
- Department of Orthopedics, Centre for Leading Medicine and Advanced Technologies of IHM, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230022, PR China; National Center for Translational Medicine (Shanghai) SHU Branch, Shanghai University, Shanghai, 200444, PR China.
| | - Tingbo Jiang
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China.
| | - Hongxia Li
- Department of Cardiology, The First Affiliated Hospital of Soochow University, 188 Shizi Street, Suzhou, Jiangsu, 215006, PR China.
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4
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Tan X, Zhang J, Heng Y, Chen L, Wang Y, Wu S, Liu X, Xu B, Yu Z, Gu R. Locally delivered hydrogels with controlled release of nanoscale exosomes promote cardiac repair after myocardial infarction. J Control Release 2024; 368:303-317. [PMID: 38417558 DOI: 10.1016/j.jconrel.2024.02.035] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2023] [Revised: 01/29/2024] [Accepted: 02/24/2024] [Indexed: 03/01/2024]
Abstract
Compared with stem cells, exosomes as a kind of nanoscale carriers intrinsically loaded with diverse bioactive molecules, which had the advantages of high safety, small size, and ethical considerations in the treatment of myocardial infarction, but there are still problems such as impaired stability and rapid dissipation. Here, we introduce a bioengineered injectable hyaluronic acid hydrogel designed to optimize local delivery efficiency of trophoblast stem cells derived-exosomes. Its hyaluronan components adeptly emulates the composition and modulus of pericardial fluid, meanwhile preserving the bioactivity of nanoscale exosomes. Additionally, a meticulously designed hyperbranched polymeric cross-linker facilitates a gentle cross-linking process among hyaluronic acid molecules, with disulfide bonds in its molecular framework enhancing biodegradability and conferring a unique controlled release capability. This innovative hydrogel offers the added advantage of minimal invasiveness during administration into the pericardial space, greatly extending the retention of exosomes within the myocardial region. In vivo, this hydrogel has consistently demonstrated its efficacy in promoting cardiac recovery, inducing anti-fibrotic, anti-inflammatory, angiogenic, and anti-remodeling effects, ultimately leading to a substantial improvement in cardiac function. Furthermore, the implementation of single-cell RNA sequencing has elucidated that the pivotal mechanism underlying enhanced cardiac function primarily results from the promoted clearance of apoptotic cells by myocardial fibroblasts.
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Affiliation(s)
- Xi Tan
- Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, 358 Zhongshan Road, 210008 Nanjing, China
| | - Jing Zhang
- State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, 30 Puzhu South Road, 211816 Nanjing, China
| | - Yongyuan Heng
- State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, 30 Puzhu South Road, 211816 Nanjing, China
| | - Lin Chen
- Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, 358 Zhongshan Road, 210008 Nanjing, China
| | - Yi Wang
- Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, 358 Zhongshan Road, 210008 Nanjing, China
| | - Shaojun Wu
- Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 358 Zhongshan Road, 210008 Nanjing, China
| | - Xiaoli Liu
- Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 358 Zhongshan Road, 210008 Nanjing, China
| | - Biao Xu
- Department of Cardiology, Nanjing Drum Tower Hospital, Nanjing Drum Tower Hospital Clinical College, Nanjing University of Chinese Medicine, 358 Zhongshan Road, 210008 Nanjing, China.
| | - Ziyi Yu
- State Key Laboratory of Materials-Oriented Chemical Engineering, College of Chemical Engineering, Nanjing Tech University, 30 Puzhu South Road, 211816 Nanjing, China.
| | - Rong Gu
- Department of Cardiology, Nanjing Drum Tower Hospital, State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, 358 Zhongshan Road, 210008 Nanjing, China.
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5
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Wang Q, Spurlock B, Liu J, Qian L. Fibroblast Reprogramming in Cardiac Repair. JACC Basic Transl Sci 2024; 9:145-160. [PMID: 38362341 PMCID: PMC10864899 DOI: 10.1016/j.jacbts.2023.06.012] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2023] [Revised: 06/22/2023] [Accepted: 06/27/2023] [Indexed: 02/17/2024]
Abstract
Cardiovascular disease is one of the major causes of death worldwide. Limited proliferative capacity of adult mammalian cardiomyocytes has prompted researchers to exploit regenerative therapy after myocardial injury, such as myocardial infarction, to attenuate heart dysfunction caused by such injury. Direct cardiac reprogramming is a recently emerged promising approach to repair damaged myocardium by directly converting resident cardiac fibroblasts into cardiomyocyte-like cells. The achievement of in vivo direct reprogramming of fibroblasts has been shown, by multiple laboratories independently, to improve cardiac function and mitigate fibrosis post-myocardial infarction, which holds great potential for clinical application. There have been numerous pieces of valuable work in both basic and translational research to enhance our understanding and continued refinement of direct cardiac reprogramming in recent years. However, there remain many challenges to overcome before we can truly take advantage of this technique to treat patients with ischemic cardiac diseases. Here, we review recent progress of fibroblast reprogramming in cardiac repair, including the optimization of several reprogramming strategies, mechanistic exploration, and translational efforts, and we make recommendations for future research to further understand and translate direct cardiac reprogramming from bench to bedside. Challenges relating to these efforts will also be discussed.
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Affiliation(s)
- Qiaozi Wang
- Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Brian Spurlock
- Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Jiandong Liu
- Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
| | - Li Qian
- Department of Pathology and Laboratory Medicine, McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina, USA
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6
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Yang Y, Johnson J, Troupes CD, Feldsott EA, Kraus L, Megill E, Bian Z, Asangwe N, Kino T, Eaton DM, Wang T, Wagner M, Ma L, Bryan C, Wallner M, Kubo H, Berretta RM, Khan M, Wang H, Kishore R, Houser SR, Mohsin S. miR-182/183-Rasa1 axis induced macrophage polarization and redox regulation promotes repair after ischemic cardiac injury. Redox Biol 2023; 67:102909. [PMID: 37801856 PMCID: PMC10570148 DOI: 10.1016/j.redox.2023.102909] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 09/26/2023] [Indexed: 10/08/2023] Open
Abstract
Few therapies have produced significant improvement in cardiac structure and function after ischemic cardiac injury (ICI). Our possible explanation is activation of local inflammatory responses negatively impact the cardiac repair process following ischemic injury. Factors that can alter immune response, including significantly altered cytokine levels in plasma and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI is a valid strategy for reducing infarct size and damage after myocardial injury. Our previous studies showed that cortical bone stem cells (CBSCs) possess reparative effects after ICI. In our current study, we have identified that the beneficial effects of CBSCs appear to be mediated by miRNA in their extracellular vesicles (CBSC-EV). Our studies showed that CBSC-EV treated animals demonstrated reduced scar size, attenuated structural remodeling, and improved cardiac function versus saline treated animals. These effects were linked to the alteration of immune response, with significantly altered cytokine levels in plasma, and polarization of macrophages and T cells towards a pro-reparative phenotype in the myocardium post-MI. Our detailed in vitro studies demonstrated that CBSC-EV are enriched in miR-182/183 that mediates the pro-reparative polarization and metabolic reprogramming in macrophages, including enhanced OXPHOS rate and reduced ROS, via Ras p21 protein activator 1 (RASA1) axis under Lipopolysaccharides (LPS) stimulation. In summary, CBSC-EV deliver unique molecular cargoes, such as enriched miR-182/183, that modulate the immune response after ICI by regulating macrophage polarization and metabolic reprogramming to enhance repair.
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Affiliation(s)
- Yijun Yang
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Jaslyn Johnson
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Constantine D Troupes
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Eric A Feldsott
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Lindsay Kraus
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Emily Megill
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Zilin Bian
- Tandon School of Engineering, New York University, NY, United States
| | - Ngefor Asangwe
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Tabito Kino
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Deborah M Eaton
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Tao Wang
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Marcus Wagner
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Lena Ma
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Christopher Bryan
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Markus Wallner
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States; Division of Cardiology, Medical University of Graz, 8036, Graz, Austria
| | - Hajime Kubo
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Remus M Berretta
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Mohsin Khan
- Center for Metabolic Disease Research (CMDR), Temple University Lewis Katz School of Medicine, PA, United States
| | - Hong Wang
- Center for Metabolic Disease Research (CMDR), Temple University Lewis Katz School of Medicine, PA, United States
| | - Raj Kishore
- Center for Translational Medicine, Temple University Lewis Katz School of Medicine, PA, United States
| | - Steven R Houser
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States
| | - Sadia Mohsin
- Cardiovascular Research Center (CVRC), Temple University Lewis Katz School of Medicine, PA, United States.
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7
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Zhang X, Aggarwal P, Broeckel U, Abassi YA. Enhancing the functional maturity of hiPSC-derived cardiomyocytes to assess inotropic compounds. J Pharmacol Toxicol Methods 2023; 123:107282. [PMID: 37419294 DOI: 10.1016/j.vascn.2023.107282] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2023] [Revised: 05/19/2023] [Accepted: 07/04/2023] [Indexed: 07/09/2023]
Abstract
Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) present an attractive in vitro platform to model safety and toxicity assessments-notably screening pro-arrhythmic compounds. The utility of the platform is stymied by a hiPSC-CM contractile apparatus and calcium handling mechanism akin to fetal phenotypes, evidenced by a negative force-frequency relationship. As such, hiPSC-CMs are limited in their ability to assess compounds that modulate contraction mediated by ionotropic compounds (Robertson, Tran, & George, 2013). To address this limitation, we utilize Agilent's xCELLigence Real-Time Cell Analyzer ePacer (RTCA ePacer) to enhance hiPSC-CM functional maturity. A continuous, progressive increase of electrical pacing is applied to hiPSC-CMs for up to 15 days. Contraction and viability are recorded by measurement of impedance using the RTCA ePacer. Our data confirms hiPSC-CMs inherently demonstrate a negative impedance amplitude frequency that is reversed after long-term electrical pacing. The data also indicate positive inotropic compounds increase the contractility of paced cardiomyocytes and calcium handling machinery is improved. Increased expression of genes critical to cardiomyocyte maturation further underscores the maturity of paced cells. In summary, our data suggest the application of continuous electrical pacing can functionally mature hiPSC-CMs, enhancing cellular response to positive inotropic compounds and improving calcium handling. SUMMARY: Long-term electrical stimulation of hiPSC-CM leads to functional maturation enabling predictive assessment of inotropic compounds.
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Molinaro C, Scalise M, Leo I, Salerno L, Sabatino J, Salerno N, De Rosa S, Torella D, Cianflone E, Marino F. Polarizing Macrophage Functional Phenotype to Foster Cardiac Regeneration. Int J Mol Sci 2023; 24:10747. [PMID: 37445929 DOI: 10.3390/ijms241310747] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 06/22/2023] [Accepted: 06/26/2023] [Indexed: 07/15/2023] Open
Abstract
There is an increasing interest in understanding the connection between the immune and cardiovascular systems, which are highly integrated and communicate through finely regulated cross-talking mechanisms. Recent evidence has demonstrated that the immune system does indeed have a key role in the response to cardiac injury and in cardiac regeneration. Among the immune cells, macrophages appear to have a prominent role in this context, with different subtypes described so far that each have a specific influence on cardiac remodeling and repair. Similarly, there are significant differences in how the innate and adaptive immune systems affect the response to cardiac damage. Understanding all these mechanisms may have relevant clinical implications. Several studies have already demonstrated that stem cell-based therapies support myocardial repair. However, the exact role that cardiac macrophages and their modulation may have in this setting is still unclear. The current need to decipher the dual role of immunity in boosting both heart injury and repair is due, at least for a significant part, to unresolved questions related to the complexity of cardiac macrophage phenotypes. The aim of this review is to provide an overview on the role of the immune system, and of macrophages in particular, in the response to cardiac injury and to outline, through the modulation of the immune response, potential novel therapeutic strategies for cardiac regeneration.
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Affiliation(s)
- Claudia Molinaro
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Mariangela Scalise
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Isabella Leo
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Luca Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Jolanda Sabatino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Nadia Salerno
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Salvatore De Rosa
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Daniele Torella
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy
| | - Fabiola Marino
- Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
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9
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Lim S, Kim SW, Kim IK, Song BW, Lee S. Organ-on-a-chip: Its use in cardiovascular research. Clin Hemorheol Microcirc 2022; 83:315-339. [DOI: 10.3233/ch-221428] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Organ-on-a-chip (OOAC) has attracted great attention during the last decade as a revolutionary alternative to conventional animal models. This cutting-edge technology has also brought constructive changes to the field of cardiovascular research. The cardiovascular system, especially the heart as a well-protected vital organ, is virtually impossible to replicate in vitro with conventional approaches. This made scientists assume that they needed to use animal models for cardiovascular research. However, the frequent failure of animal models to correctly reflect the native cardiovascular system necessitated a search for alternative platforms for preclinical studies. Hence, as a promising alternative to conventional animal models, OOAC technology is being actively developed and tested in a wide range of biomedical fields, including cardiovascular research. Therefore, in this review, the current literature on the use of OOACs for cardiovascular research is presented with a focus on the basis for using OOACs, and what has been specifically achieved by using OOACs is also discussed. By providing an overview of the current status of OOACs in cardiovascular research and its future perspectives, we hope that this review can help to develop better and optimized research strategies for cardiovascular diseases (CVDs) as well as identify novel applications of OOACs in the near future.
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Affiliation(s)
- Soyeon Lim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea
| | - Sang Woo Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea
| | - Il-Kwon Kim
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea
| | - Byeong-Wook Song
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea
| | - Seahyoung Lee
- Institute for Bio-Medical Convergence, College of Medicine, Catholic Kwandong University, Gangneung, Gangwon-do, Republic of Korea
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10
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Sharma V, Manhas A, Gupta S, Dikshit M, Jagavelu K, Verma RS. Fabrication, characterization and in vivo assessment of cardiogel loaded chitosan patch for myocardial regeneration. Int J Biol Macromol 2022; 222:3045-3056. [DOI: 10.1016/j.ijbiomac.2022.10.079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 10/06/2022] [Accepted: 10/09/2022] [Indexed: 11/05/2022]
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11
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Xu Q, Sigen A, Wang W. Injectable Hydrogels as a Stem Cell Delivery Platform for Wound Healing. MULTIFUNCTIONAL HYDROGELS FOR BIOMEDICAL APPLICATIONS 2022:323-355. [DOI: 10.1002/9783527825820.ch14] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2025]
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12
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Maria Cherian R, Prajapati C, Penttinen K, Häkli M, Koivisto JT, Pekkanen-Mattila M, Aalto-Setälä K. Fluorescent hiPSC-derived MYH6-mScarlet cardiomyocytes for real-time tracking, imaging, and cardiotoxicity assays. Cell Biol Toxicol 2022; 39:145-163. [PMID: 35870039 PMCID: PMC10042918 DOI: 10.1007/s10565-022-09742-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Accepted: 06/29/2022] [Indexed: 11/02/2022]
Abstract
AbstractHuman induced pluripotent stem cell derived cardiomyocytes (hiPSC-CMs) hold great potential in the cardiovascular field for human disease modeling, drug development, and regenerative medicine. However, multiple hurdles still exist for the effective utilization of hiPSC-CMs as a human-based experimental platform that can be an alternative to the current animal models. To further expand their potential as a research tool and bridge the translational gap, we have generated a cardiac-specific hiPSC reporter line that differentiates into fluorescent CMs using CRISPR-Cas9 genome editing technology. The CMs illuminated with the mScarlet fluorescence enable their non-invasive continuous tracking and functional cellular phenotyping, offering a real-time 2D/3D imaging platform. Utilizing the reporter CMs, we developed an imaging-based cardiotoxicity screening system that can monitor distinct drug-induced structural toxicity and CM viability in real time. The reporter fluorescence enabled visualization of sarcomeric disarray and displayed a drug dose–dependent decrease in its fluorescence. The study also has demonstrated the reporter CMs as a biomaterial cytocompatibility analysis tool that can monitor dynamic cell behavior and maturity of hiPSC-CMs cultured in various biomaterial scaffolds. This versatile cardiac imaging tool that enables real time tracking and high-resolution imaging of CMs has significant potential in disease modeling, drug screening, and toxicology testing.
Graphical abstract
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13
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Gupta S, Kawaguchi R, Heinrichs E, Gallardo S, Castellanos S, Mandric I, Novitch BG, Butler SJ. In vitro atlas of dorsal spinal interneurons reveals Wnt signaling as a critical regulator of progenitor expansion. Cell Rep 2022; 40:111119. [PMID: 35858555 PMCID: PMC9414195 DOI: 10.1016/j.celrep.2022.111119] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 04/12/2022] [Accepted: 06/28/2022] [Indexed: 11/03/2022] Open
Abstract
Restoring sensation after injury or disease requires a reproducible method for generating large quantities of bona fide somatosensory interneurons. Toward this goal, we assess the mechanisms by which dorsal spinal interneurons (dIs; dI1-dI6) can be derived from mouse embryonic stem cells (mESCs). Using two developmentally relevant growth factors, retinoic acid (RA) and bone morphogenetic protein (BMP) 4, we recapitulate the complete in vivo program of dI differentiation through a neuromesodermal intermediate. Transcriptional profiling reveals that mESC-derived dIs strikingly resemble endogenous dIs, with the correct molecular and functional signatures. We further demonstrate that RA specifies dI4-dI6 fates through a default multipotential state, while the addition of BMP4 induces dI1-dI3 fates and activates Wnt signaling to enhance progenitor proliferation. Constitutively activating Wnt signaling permits the dramatic expansion of neural progenitor cultures. These cultures retain the capacity to differentiate into diverse populations of dIs, thereby providing a method of increasing neuronal yield.
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Affiliation(s)
- Sandeep Gupta
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA.
| | - Riki Kawaguchi
- Department of Psychiatry, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Eric Heinrichs
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Genetics and Genomics Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Salena Gallardo
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Molecular Biology Interdepartmental Graduate Program, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Stephanie Castellanos
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; CIRM Bridges to Research Program, California State University, Northridge, Los Angeles, CA, USA
| | - Igor Mandric
- Department of Computer Science, Samueli School of Engineering, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Bennett G Novitch
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual & Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA
| | - Samantha J Butler
- Department of Neurobiology, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA; Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research, University of California, Los Angeles, Los Angeles, CA 90095, USA; Intellectual & Developmental Disabilities Research Center, University of California, Los Angeles, Los Angeles, CA 90095, USA.
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Rashid SA, Blanchard AT, Combs JD, Fernandez N, Dong Y, Cho HC, Salaita K. DNA Tension Probes Show that Cardiomyocyte Maturation Is Sensitive to the Piconewton Traction Forces Transmitted by Integrins. ACS NANO 2022; 16:5335-5348. [PMID: 35324164 PMCID: PMC11238821 DOI: 10.1021/acsnano.1c04303] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/14/2023]
Abstract
Cardiac muscle cells (CMCs) are the unit cells that comprise the heart. CMCs go through different stages of differentiation and maturation pathways to fully mature into beating cells. These cells can sense and respond to mechanical cues through receptors such as integrins which influence maturation pathways. For example, cell traction forces are important for the differentiation and development of functional CMCs, as CMCs cultured on varying substrate stiffness function differently. Most work in this area has focused on understanding the role of bulk extracellular matrix stiffness in mediating the functional fate of CMCs. Given that stiffness sensing mechanisms are mediated by individual integrin receptors, an important question in this area pertains to the specific magnitude of integrin piconewton (pN) forces that can trigger CMC functional maturation. To address this knowledge gap, we used DNA adhesion tethers that rupture at specific thresholds of force (∼12, ∼56, and ∼160 pN) to test whether capping peak integrin tension to specific magnitudes affects CMC function. We show that adhesion tethers with greater force tolerance lead to functionally mature CMCs as determined by morphology, twitching frequency, transient calcium flux measurements, and protein expression (F-actin, vinculin, α-actinin, YAP, and SERCA2a). Additionally, sarcomeric actinin alignment and multinucleation were significantly enhanced as the mechanical tolerance of integrin tethers was increased. Taken together, the results show that CMCs harness defined pN integrin forces to influence early stage development. This study represents an important step toward biophysical characterization of the contribution of pN forces in early stage cardiac differentiation.
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Affiliation(s)
- Sk Aysha Rashid
- Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
| | - Aaron T Blanchard
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, Georgia 30332, United States
| | - J Dale Combs
- Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
| | - Natasha Fernandez
- Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1405 Clifton Road NE, Atlanta, Georgia 30322, United States
| | - Yixiao Dong
- Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
| | - Hee Cheol Cho
- Division of Pediatric Cardiology, Department of Pediatrics, Emory University School of Medicine and Children's Healthcare of Atlanta, 1405 Clifton Road NE, Atlanta, Georgia 30322, United States
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, Georgia 30332, United States
| | - Khalid Salaita
- Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, Georgia 30322, United States
- Wallace H. Coulter Department of Biomedical Engineering, Georgia Institute of Technology and Emory University, 313 Ferst Drive, Atlanta, Georgia 30332, United States
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15
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Cossu G, Tonlorenzi R, Brunelli S, Sampaolesi M, Messina G, Azzoni E, Benedetti S, Biressi S, Bonfanti C, Bragg L, Camps J, Cappellari O, Cassano M, Ciceri F, Coletta M, Covarello D, Crippa S, Cusella-De Angelis MG, De Angelis L, Dellavalle A, Diaz-Manera J, Galli D, Galli F, Gargioli C, Gerli MFM, Giacomazzi G, Galvez BG, Hoshiya H, Guttinger M, Innocenzi A, Minasi MG, Perani L, Previtali SC, Quattrocelli M, Ragazzi M, Roostalu U, Rossi G, Scardigli R, Sirabella D, Tedesco FS, Torrente Y, Ugarte G. Mesoangioblasts at 20: From the embryonic aorta to the patient bed. Front Genet 2022; 13:1056114. [PMID: 36685855 PMCID: PMC9845585 DOI: 10.3389/fgene.2022.1056114] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2022] [Accepted: 10/31/2022] [Indexed: 01/06/2023] Open
Abstract
In 2002 we published an article describing a population of vessel-associated progenitors that we termed mesoangioblasts (MABs). During the past decade evidence had accumulated that during muscle development and regeneration things may be more complex than a simple sequence of binary choices (e.g., dorsal vs. ventral somite). LacZ expressing fibroblasts could fuse with unlabelled myoblasts but not among themselves or with other cell types. Bone marrow derived, circulating progenitors were able to participate in muscle regeneration, though in very small percentage. Searching for the embryonic origin of these progenitors, we identified them as originating at least in part from the embryonic aorta and, at later stages, from the microvasculature of skeletal muscle. While continuing to investigate origin and fate of MABs, the fact that they could be expanded in vitro (also from human muscle) and cross the vessel wall, suggested a protocol for the cell therapy of muscular dystrophies. We tested this protocol in mice and dogs before proceeding to the first clinical trial on Duchenne Muscular Dystrophy patients that showed safety but minimal efficacy. In the last years, we have worked to overcome the problem of low engraftment and tried to understand their role as auxiliary myogenic progenitors during development and regeneration.
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Affiliation(s)
- Giulio Cossu
- Division of Cell Matrix Biology and Regenerative Medicine. University of Manchester, Manchester, United Kingdom
- Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
- Muscle Research Unit, Charité Medical Faculty and Max Delbrück Center, Berlin, Germany
- *Correspondence: Giulio Cossu, ; Rossana Tonlorenzi, ; Silvia Brunelli, ; Maurilio Sampaolesi, ; Graziella Messina,
| | - Rossana Tonlorenzi
- Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
- *Correspondence: Giulio Cossu, ; Rossana Tonlorenzi, ; Silvia Brunelli, ; Maurilio Sampaolesi, ; Graziella Messina,
| | - Silvia Brunelli
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
- *Correspondence: Giulio Cossu, ; Rossana Tonlorenzi, ; Silvia Brunelli, ; Maurilio Sampaolesi, ; Graziella Messina,
| | - Maurilio Sampaolesi
- Translational Cardiomyology Laboratory, Stem Cell and Developmental Biology Unit, Department of Development and Regeneration, KU Leuven, Leuven, Belgium
- Histology and Medical Embryology Unit, Department of Anatomy, Forensic Medicine and Orthopaedics, Sapienza University, Rome, Italy
- *Correspondence: Giulio Cossu, ; Rossana Tonlorenzi, ; Silvia Brunelli, ; Maurilio Sampaolesi, ; Graziella Messina,
| | - Graziella Messina
- Department of Biosciences, University of Milan, Milan, Italy
- *Correspondence: Giulio Cossu, ; Rossana Tonlorenzi, ; Silvia Brunelli, ; Maurilio Sampaolesi, ; Graziella Messina,
| | - Emanuele Azzoni
- School of Medicine and Surgery, University of Milano Bicocca, Milan, Italy
| | - Sara Benedetti
- UCL Great Ormond Street Institute of Child Health and NIHR GOSH Biomedical Research Centre, London, United Kingdom
| | - Stefano Biressi
- Department of Cellular, Computational and Integrative Biology (CIBIO) and Dulbecco Telethon Institute, University of Trento, Trento, Italy
| | - Chiara Bonfanti
- Department of Biosciences, University of Milan, Milan, Italy
| | - Laricia Bragg
- Division of Cell Matrix Biology and Regenerative Medicine. University of Manchester, Manchester, United Kingdom
| | - Jordi Camps
- Bayer AG, Research and Development, Pharmaceuticals, Berlin, Germany
| | - Ornella Cappellari
- Department of Pharmacy-Drug Sciences, University of Bari “Aldo Moro”, Bari, Italy
| | | | - Fabio Ciceri
- Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
| | - Marcello Coletta
- Histology and Medical Embryology Unit, Department of Anatomy, Forensic Medicine and Orthopaedics, Sapienza University, Rome, Italy
| | | | - Stefania Crippa
- San Raffaele-Telethon Institute of Gene Theray, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Luciana De Angelis
- Histology and Medical Embryology Unit, Department of Anatomy, Forensic Medicine and Orthopaedics, Sapienza University, Rome, Italy
| | | | - Jordi Diaz-Manera
- John Walton Muscular Dystrophy Research Centre, Newcastle University, United Kingdom
| | - Daniela Galli
- Department of Medicine and Surgery, University of Parma, Parma, Italy
| | - Francesco Galli
- Division of Cell Matrix Biology and Regenerative Medicine. University of Manchester, Manchester, United Kingdom
| | - Cesare Gargioli
- Department of Biology, University of Tor Vergata, Rome, Italy
| | - Mattia F. M. Gerli
- UCL Department of Surgical Biotechnology and Great Ormond Street Institute of Child Health, London, United Kingdom
| | | | - Beatriz G. Galvez
- Department of Biochemistry and Molecular Biology, Faculty of Pharmacy, Universidad Complutense de Madrid, Madrid, Spain
| | | | | | - Anna Innocenzi
- Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
| | - M. Giulia Minasi
- Lavitaminasi, Clinical Nutrition and Reproductive Medicine, Rome, Italy
| | - Laura Perani
- Division of Neuroscience, IRCCS Ospedale San Raffaele, Milan, Italy
| | | | - Mattia Quattrocelli
- Division of Molecular Cardiovascular Biology, University of Cincinnati, Cincinnati, OH, United States
| | | | - Urmas Roostalu
- Roche Institute for Translational Bioengineering (ITB), pRED Basel, Basel, Switzerland
| | - Giuliana Rossi
- Institute of Translational Pharmacology, National Research Council, Rome, Italy
| | - Raffaella Scardigli
- Columbia Stem Cell Initiative, Department of Rehabilitation and Regenerative Medicine, Columbia University, New York, United States
| | - Dario Sirabella
- University College London, Great Ormond Street Hospital for Children and the Francis Crick Institute, London, United Kingdom
| | - Francesco Saverio Tedesco
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile
| | - Yvan Torrente
- UCL Great Ormond Street Institute of Child Health and NIHR GOSH Biomedical Research Centre, London, United Kingdom
| | - Gonzalo Ugarte
- Laboratory of Neuroscience, Faculty of Chemistry and Biology, University of Santiago de Chile, Santiago, Chile
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16
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Schena GJ, Murray EK, Hildebrand AN, Headrick AL, Yang Y, Koch KA, Kubo H, Eaton D, Johnson J, Berretta R, Mohsin S, Kishore R, McKinsey TA, Elrod JW, Houser SR. Cortical bone stem cell-derived exosomes' therapeutic effect on myocardial ischemia-reperfusion and cardiac remodeling. Am J Physiol Heart Circ Physiol 2021; 321:H1014-H1029. [PMID: 34623184 PMCID: PMC8793944 DOI: 10.1152/ajpheart.00197.2021] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 09/27/2021] [Accepted: 09/27/2021] [Indexed: 12/20/2022]
Abstract
Heart failure is the one of the leading causes of death in the United States. Heart failure is a complex syndrome caused by numerous diseases, including severe myocardial infarction (MI). MI occurs after an occlusion of a cardiac artery causing downstream ischemia. MI is followed by cardiac remodeling involving extensive remodeling and fibrosis, which, if the original insult is severe or prolonged, can ultimately progress into heart failure. There is no "cure" for heart failure because therapies to regenerate dead tissue are not yet available. Previous studies have shown that in both post-MI and post-ischemia-reperfusion (I/R) models of heart failure, administration of cortical bone stem cell (CBSC) treatment leads to a reduction in scar size and improved cardiac function. Our first study investigated the ability of mouse CBSC-derived exosomes (mCBSC-dEXO) to recapitulate mouse CBSCs (mCBSC) therapeutic effects in a 24-h post-I/R model. This study showed that injection of mCBSCs and mCBSC-dEXOs into the ischemic region of an infarct had a protective effect against I/R injury. mCBSC-dEXOs recapitulated the effects of CBSC treatment post-I/R, indicating exosomes are partly responsible for CBSC's beneficial effects. To examine if exosomes decrease fibrotic activation, adult rat ventricular fibroblasts (ARVFs) and adult human cardiac fibroblasts (NHCFs) were treated with transforming growth factor β (TGFβ) to activate fibrotic signaling before treatment with mCBSC- and human CBSC (hCBSC)-dEXOs. hCBSC-dEXOs caused a 100-fold decrease in human fibroblast activation. To further understand the signaling mechanisms regulating the protective decrease in fibrosis, we performed RNA sequencing on the NHCFs after hCBSC-dEXO treatment. The group treated with both TGFβ and exosomes showed a decrease in small nucleolar RNA (snoRNA), known to be involved with ribosome stability.NEW & NOTEWORTHY Our work is noteworthy due to the identification of factors within stem cell-derived exosomes (dEXOs) that alter fibroblast activation through the hereto-unknown mechanism of decreasing small nucleolar RNA (snoRNA) signaling within cardiac fibroblasts. The study also shows that the injection of stem cells or a stem-cell-derived exosome therapy at the onset of reperfusion elicits cardioprotection, emphasizing the importance of early treatment in the post-ischemia-reperfusion (I/R) wounded heart.
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Affiliation(s)
- Giana J Schena
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Emma K Murray
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Alycia N Hildebrand
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Alaina L Headrick
- Division of Cardiology & Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Yijun Yang
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Keith A Koch
- Division of Cardiology & Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - Hajime Kubo
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Deborah Eaton
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Jaslyn Johnson
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Remus Berretta
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Sadia Mohsin
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Raj Kishore
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Timothy A McKinsey
- Division of Cardiology & Consortium for Fibrosis Research and Translation, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado
| | - John W Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, Pennsylvania
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17
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Yousefi-Ahmadipour A, Asadi F, Pirsadeghi A, Nazeri N, Vahidi R, Abazari MF, Afgar A, Mirzaei-Parsa MJ. Current Status of Stem Cell Therapy and Nanofibrous Scaffolds in Cardiovascular Tissue Engineering. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00230-1] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
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18
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Recent Advances in Cardiac Tissue Engineering for the Management of Myocardium Infarction. Cells 2021; 10:cells10102538. [PMID: 34685518 PMCID: PMC8533887 DOI: 10.3390/cells10102538] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2021] [Revised: 09/16/2021] [Accepted: 09/21/2021] [Indexed: 12/26/2022] Open
Abstract
Myocardium Infarction (MI) is one of the foremost cardiovascular diseases (CVDs) causing death worldwide, and its case numbers are expected to continuously increase in the coming years. Pharmacological interventions have not been at the forefront in ameliorating MI-related morbidity and mortality. Stem cell-based tissue engineering approaches have been extensively explored for their regenerative potential in the infarcted myocardium. Recent studies on microfluidic devices employing stem cells under laboratory set-up have revealed meticulous events pertaining to the pathophysiology of MI occurring at the infarcted site. This discovery also underpins the appropriate conditions in the niche for differentiating stem cells into mature cardiomyocyte-like cells and leads to engineering of the scaffold via mimicking of native cardiac physiological conditions. However, the mode of stem cell-loaded engineered scaffolds delivered to the site of infarction is still a challenging mission, and yet to be translated to the clinical setting. In this review, we have elucidated the various strategies developed using a hydrogel-based system both as encapsulated stem cells and as biocompatible patches loaded with cells and applied at the site of infarction.
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19
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Blume GG, Machado-Junior PAB, Simeoni RB, Bertinato GP, Tonial MS, Nagashima S, Pinho RA, de Noronha L, Olandoski M, de Carvalho KAT, Francisco JC, Guarita-Souza LC. Bone-Marrow Stem Cells and Acellular Human Amniotic Membrane in a Rat Model of Heart Failure. Life (Basel) 2021; 11:958. [PMID: 34575107 PMCID: PMC8471644 DOI: 10.3390/life11090958] [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: 08/16/2021] [Revised: 09/07/2021] [Accepted: 09/09/2021] [Indexed: 11/17/2022] Open
Abstract
Myocardial infarction (MI) remains the leading cause of cardiovascular death worldwide and a major cause of heart failure. Recent studies have suggested that cell-based therapies with bone marrow stem cells (BMSC) and human amniotic membrane (hAM) would recover the ventricular function after MI; however, the mechanisms underlying these effects are still controversial. Herein, we aimed to compare the effects of BMSC and hAM in a rat model of heart failure. MI was induced through coronary occlusion, and animals with an ejection fraction (EF) < 50% were included and randomized into three groups: control, BMSC, and hAM. The BMSC and hAM groups were implanted on the anterior ventricular wall seven days after MI, and a new echocardiographic analysis was performed on the 30th day, followed by euthanasia. The echocardiographic results after 30 days showed significant improvements on EF and left-ventricular end-sistolic and end-diastolic volumes in both BMSC and hAM groups, without significant benefits in the control group. New blood vessels, desmine-positive cells and connexin-43 expression were also elevated in both BMSC and hAM groups. These results suggest a recovery of global cardiac function with the therapeutic use of both BMSC and hAM, associated with angiogenesis and cardiomyocyte regeneration after 30 days.
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Affiliation(s)
- Gustavo Gavazzoni Blume
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Paulo André Bispo Machado-Junior
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Rossana Baggio Simeoni
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Giovana Paludo Bertinato
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Murilo Sgarbossa Tonial
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Seigo Nagashima
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Ricardo Aurino Pinho
- Laboratory of Exercise Biochemistry in Health, Graduate Program in Health Sciences, School of Medicine, Pontifícia Universidade Católica do Paraná, Curitiba 80215-901, Brazil;
| | - Lucia de Noronha
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Marcia Olandoski
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
| | - Katherine Athayde Teixeira de Carvalho
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research & Pequeno Príncipe Faculties, Curitiba 80215-901, Brazil; (K.A.T.d.C.); (J.C.F.)
| | - Julio Cesar Francisco
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, The Pelé Pequeno Príncipe Institute, Child and Adolescent Health Research & Pequeno Príncipe Faculties, Curitiba 80215-901, Brazil; (K.A.T.d.C.); (J.C.F.)
| | - Luiz Cesar Guarita-Souza
- Experimental Laboratory of Institute of Biological and Health Sciences, Pontifícia Universidade Católica do Paraná (PUCPR), Curitiba 80215-901, Brazil; (P.A.B.M.-J.); (R.B.S.); (G.P.B.); (M.S.T.); (S.N.); (L.d.N.); (M.O.); (L.C.G.-S.)
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20
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Das S, Nam H, Jang J. 3D bioprinting of stem cell-laden cardiac patch: A promising alternative for myocardial repair. APL Bioeng 2021; 5:031508. [PMID: 34368602 PMCID: PMC8318604 DOI: 10.1063/5.0030353] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2020] [Accepted: 06/01/2021] [Indexed: 12/18/2022] Open
Abstract
Stem cell-laden three-dimensional (3D) bioprinted cardiac patches offer an alternative and promising therapeutic and regenerative approach for ischemic cardiomyopathy by reversing scar formation and promoting myocardial regeneration. Numerous studies have reported using either multipotent or pluripotent stem cells or their combination for 3D bioprinting of a cardiac patch with the sole aim of restoring cardiac function by faithfully rejuvenating the cardiomyocytes and associated vasculatures that are lost to myocardial infarction. While many studies have demonstrated success in mimicking cardiomyocytes' behavior, improving cardiac function and providing new hope for regenerating heart post-myocardial infarction, some others have reported contradicting data in apparent ways. Nonetheless, all investigators in the field are speed racing toward determining a potential strategy to effectively treat losses due to myocardial infarction. This review discusses various types of candidate stem cells that possess cardiac regenerative potential, elucidating their applications and limitations. We also brief the challenges of and an update on the implementation of the state-of-the-art 3D bioprinting approach to fabricate cardiac patches and highlight different strategies to implement vascularization and augment cardiac functional properties with respect to electrophysiological similarities to native tissue.
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Affiliation(s)
- Sanskrita Das
- Department of Convergence IT Engineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea
| | - Hyoryung Nam
- Department of Convergence IT Engineering, POSTECH, 77 Cheongam-ro, Namgu, Pohang, Kyungbuk 37673, Republic of Korea
| | - Jinah Jang
- Author to whom correspondence should be addressed:
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21
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Villarreal-Leal RA, Cooke JP, Corradetti B. Biomimetic and immunomodulatory therapeutics as an alternative to natural exosomes for vascular and cardiac applications. NANOMEDICINE : NANOTECHNOLOGY, BIOLOGY, AND MEDICINE 2021; 35:102385. [PMID: 33774130 PMCID: PMC8238887 DOI: 10.1016/j.nano.2021.102385] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Revised: 02/21/2021] [Accepted: 03/03/2021] [Indexed: 02/07/2023]
Abstract
Inflammation is a central mechanism in cardiovascular diseases (CVD), where sustained oxidative stress and immune responses contribute to cardiac remodeling and impairment. Exosomes are extracellular vesicles released by cells to communicate with their surroundings and to modulate the tissue microenvironment. Recent evidence indicates their potential as cell-free immunomodulatory therapeutics for CVD, preventing cell death and fibrosis while inducing wound healing and angiogenesis. Biomimetic exosomes are semi-synthetic particles engineered using essential moieties present in natural exosomes (lipids, RNA, proteins) to reproduce their therapeutic effects while improving on scalability and standardization due to the ample range of moieties available to produce them. In this review, we provide an up-to-date description of the use of exosomes for CVD and offer our vision on the areas of opportunity for the development of biomimetic strategies. We also discuss the current limitations to overcome in the process towards their translation into clinic.
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Affiliation(s)
- Ramiro A Villarreal-Leal
- Tecnologico de Monterrey, Escuela de Medicina y Ciencias de la Salud, Monterrey, Nuevo León, Mexico
| | - John P Cooke
- RNA Therapeutics Program, Department of Cardiovascular Sciences (R.S., J.P.C.), Houston Methodist Research Institute, TX, USA; Houston Methodist DeBakey Heart and Vascular Center (J.P.C.), Houston Methodist Hospital, TX, USA
| | - Bruna Corradetti
- Department of Nanomedicine, Houston Methodist Research Institute, Houston, TX, USA; Center of NanoHealth, Swansea University Medical School, Swansea, UK.
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22
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Shapira A, Dvir T. 3D Tissue and Organ Printing-Hope and Reality. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2021; 8:2003751. [PMID: 34026444 PMCID: PMC8132062 DOI: 10.1002/advs.202003751] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/01/2020] [Revised: 12/13/2020] [Indexed: 05/02/2023]
Abstract
Three-dimensional (3D) bioprinting is an emerging, groundbreaking strategy in tissue engineering, allowing the fabrication of living constructs with an unprecedented degree of complexity and accuracy. While this technique greatly facilitates the structuring of native tissue-like architectures, many challenges still remain to be faced. In this review, the fruits of recent research that demonstrate how advanced bioprinting technologies, together with inspiring creativity, can be used to address these challenges are presented and discussed. Next, the future of the field is discussed, in terms of expected developments, as well as possible directions toward the realization of the vision of fully functional, engineered tissues, and organs. Last, a few hypothetical scenarios for the role 3D bioprinting may play in future tissue engineering are depicted, with an emphasis on its impact on tomorrow's regenerative medicine.
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Affiliation(s)
- Assaf Shapira
- Shmunis School of Biomedicine and Cancer ResearchFaculty of Life SciencesTel Aviv UniversityTel Aviv6997801Israel
| | - Tal Dvir
- Shmunis School of Biomedicine and Cancer ResearchFaculty of Life SciencesTel Aviv UniversityTel Aviv6997801Israel
- Department of Materials Science and EngineeringFaculty of EngineeringTel Aviv UniversityTel Aviv6997801Israel
- The Center for Nanoscience and NanotechnologyTel Aviv UniversityTel Aviv6997801Israel
- Sagol Center for Regenerative BiotechnologyTel Aviv UniversityTel Aviv6997801Israel
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23
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Proteomic and Glyco(proteo)mic tools in the profiling of cardiac progenitors and pluripotent stem cell derived cardiomyocytes: Accelerating translation into therapy. Biotechnol Adv 2021; 49:107755. [PMID: 33895330 DOI: 10.1016/j.biotechadv.2021.107755] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2020] [Revised: 03/15/2021] [Accepted: 04/18/2021] [Indexed: 12/14/2022]
Abstract
Research in stem cells paved the way to an enormous amount of knowledge, increasing expectations on cardio regenerative therapeutic approaches in clinic. While the first generation of clinical trials using cell-based therapies in the heart were performed with bone marrow and adipose tissue derived mesenchymal stem cells, second generation cell therapies moved towards the use of cardiac-committed cell populations, including cardiac progenitor cells and pluripotent stem cell derived cardiomyocytes. Despite all these progresses, translating the aptitudes of R&D and pre-clinical data into effective clinical treatments is still highly challenging, partially due to the demanding regulatory and safety concerns but also because of the lack of knowledge on the regenerative mechanisms of action of these therapeutic products. Thus, the need of analytical methodologies that enable a complete characterization of such complex products and a deep understanding of their therapeutic effects, at the cell and molecular level, is imperative to overcome the hurdles of these advanced therapies. Omics technologies, such as proteomics and glyco(proteo)mics workflows based on state of the art mass-spectrometry, have prompted some major breakthroughs, providing novel data on cell biology and a detailed assessment of cell based-products applied in cardiac regeneration strategies. These advanced 'omics approaches, focused on the profiling of protein and glycan signatures are excelling the identification and characterization of cell populations under study, namely unveiling pluripotency and differentiation markers, as well as paracrine mechanisms and signaling cascades involved in cardiac repair. The leading knowledge generated is supporting a more rational therapy design and the rethinking of challenges in Advanced Therapy Medicinal Products development. Herein, we review the most recent methodologies used in the fields of proteomics, glycoproteomics and glycomics and discuss their impact on the study of cardiac progenitor cells and pluripotent stem cell derived cardiomyocytes biology. How these discoveries will impact the speed up of novel therapies for cardiovascular diseases is also addressed.
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24
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Park TY, Maeng SW, Jeon EY, Joo KI, Cha HJ. Adhesive protein-based angiogenesis-mimicking spatiotemporal sequential release of angiogenic factors for functional regenerative medicine. Biomaterials 2021; 272:120774. [PMID: 33798963 DOI: 10.1016/j.biomaterials.2021.120774] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2020] [Revised: 02/18/2021] [Accepted: 03/21/2021] [Indexed: 01/08/2023]
Abstract
Damaged vascular structures after critical diseases are difficult to completely restore to their original conditions without specific treatments. Thus, therapeutic angiogenesis has been spotlighted as an attractive strategy. However, effective strategies for mimicking angiogenic processes in the body have not yet been developed. In the present work, we developed a bioengineered mussel adhesive protein (MAP)-based novel therapeutic angiogenesis platform capable of spatiotemporally releasing angiogenic growth factors to target disease sites with high viscosity and strong adhesiveness in a mucus-containing environment with curvature. Polycationic MAP formed complex coacervate liquid microdroplets with polyanionic hyaluronic acid and subsequently gelated into microparticles. Platelet-derived growth factor (PDGF), which is a late-phase angiogenic factor, was efficiently encapsulated during the process of coacervate microparticle formation. These PDGF-loaded microparticles were blended with vascular endothelial growth factor (VEGF), which is the initial-phase angiogenic factor, in MAP-based pregel solution and finally crosslinked in situ into a hydrogel at the desired site. The microparticle-based angiogenic-molecule spatiotemporal sequential (MASS) release platform showed good adhesion and underwater durability, and its elasticity was close to that of target tissue. Using two in vivo critical models, i.e., full-thickness excisional wound and myocardial infarction models, the MASS release platform was evaluated for its in vivo feasibility as an angiogenesis-inducing platform and demonstrated effective angiogenesis as well as functional regenerative efficacy. Based on these superior physicochemical characteristics, the developed MASS release platform could be successfully applied in many biomedical practices as a waterproof bioadhesive with the capability for the spatiotemporal delivery of angiogenic molecules in the treatment of ischemic diseases.
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Affiliation(s)
- Tae Yoon Park
- Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Seong-Woo Maeng
- Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Eun Young Jeon
- Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea
| | - Kye Il Joo
- Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea; Division of Chemical Engineering and Materials Science, Ewha Womans University, Seoul, 03760, Republic of Korea
| | - Hyung Joon Cha
- Department of Chemical Engineering, Pohang University of Science and Technology, Pohang, 37673, Republic of Korea.
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25
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Agarwal T, Fortunato GM, Hann SY, Ayan B, Vajanthri KY, Presutti D, Cui H, Chan AHP, Costantini M, Onesto V, Di Natale C, Huang NF, Makvandi P, Shabani M, Maiti TK, Zhang LG, De Maria C. Recent advances in bioprinting technologies for engineering cardiac tissue. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 124:112057. [PMID: 33947551 DOI: 10.1016/j.msec.2021.112057] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/12/2021] [Revised: 03/09/2021] [Accepted: 03/12/2021] [Indexed: 12/12/2022]
Abstract
Annually increasing incidence of cardiac-related disorders and cardiac tissue's minimal regenerative capacity have motivated the researchers to explore effective therapeutic strategies. In the recent years, bioprinting technologies have witnessed a great wave of enthusiasm and have undergone steady advancements over a short period, opening the possibilities for recreating engineered functional cardiac tissue models for regenerative and diagnostic applications. With this perspective, the current review delineates recent developments in the sphere of engineered cardiac tissue fabrication, using traditional and advanced bioprinting strategies. The review also highlights different printing ink formulations, available cellular opportunities, and aspects of personalized medicines in the context of cardiac tissue engineering and bioprinting. On a concluding note, current challenges and prospects for further advancements are also discussed.
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Affiliation(s)
- Tarun Agarwal
- Department of Biotechnology, Indian Institute of Technology Kharagpur, West Bengal 721302, India
| | - Gabriele Maria Fortunato
- Research Center "E. Piaggio" and Department of Information Engineering, University of Pisa, Largo Lucio Lazzarino 1, 56122 Pisa, Italy
| | - Sung Yun Hann
- Department of Mechanical and Aerospace Engineering, The George Washington University, Washington, DC 20052, USA
| | - Bugra Ayan
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
| | - Kiran Yellappa Vajanthri
- School of Biomedical Engineering, Indian Institute of Technology Banaras Hindu University Varanasi, Uttar Pradesh 221005, India
| | - Dario Presutti
- Institute of Physical Chemistry - Polish Academy of Sciences, Warsaw, Poland
| | - Haitao Cui
- Department of Mechanical and Aerospace Engineering, The George Washington University, Washington, DC 20052, USA
| | - Alex H P Chan
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA
| | - Marco Costantini
- Institute of Physical Chemistry - Polish Academy of Sciences, Warsaw, Poland
| | - Valentina Onesto
- Institute of Nanotechnology, National Research Council (CNR-NANOTEC), Campus Ecotekne, via Monteroni, Lecce 73100, Italy
| | - Concetta Di Natale
- Center for Advanced Biomaterial for Health Care (CABHC), Istituto Italiano di Tecnologia, Naples, Italy; Interdisciplinary Research Centre on Biomaterials (CRIB), University of Naples Federico II, P.leTecchio 80, Naples 80125, Italy
| | - Ngan F Huang
- Department of Cardiothoracic Surgery, Stanford University, Stanford, CA, USA; Stanford Cardiovascular Institute, Stanford University, Stanford, CA, USA; Veterans Affairs Palo Alto Health Care System, Palo Alto, CA, USA
| | - Pooyan Makvandi
- Center for Materials Interface, Istituto Italiano di Tecnologia, Pontedera 56025, Pisa, Italy
| | - Majid Shabani
- Center for Materials Interface, Istituto Italiano di Tecnologia, Pontedera 56025, Pisa, Italy
| | - Tapas Kumar Maiti
- Department of Biotechnology, Indian Institute of Technology Kharagpur, West Bengal 721302, India.
| | - Lijie Grace Zhang
- Department of Mechanical and Aerospace Engineering, The George Washington University, Washington, DC 20052, USA; Department of Electrical and Computer Engineering, The George Washington University, Washington, DC 20052, USA; Department of Biomedical Engineering, The George Washington University, Washington, DC 20052, USA; Department of Medicine, The George Washington University, Washington, DC 20052, USA.
| | - Carmelo De Maria
- Research Center "E. Piaggio" and Department of Information Engineering, University of Pisa, Largo Lucio Lazzarino 1, 56122 Pisa, Italy.
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26
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Guide Cells Support Muscle Regeneration and Affect Neuro-Muscular Junction Organization. Int J Mol Sci 2021; 22:ijms22041939. [PMID: 33669272 PMCID: PMC7920023 DOI: 10.3390/ijms22041939] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 02/04/2021] [Accepted: 02/05/2021] [Indexed: 12/20/2022] Open
Abstract
Muscular regeneration is a complex biological process that occurs during acute injury and chronic degeneration, implicating several cell types. One of the earliest events of muscle regeneration is the inflammatory response, followed by the activation and differentiation of muscle progenitor cells. However, the process of novel neuromuscular junction formation during muscle regeneration is still largely unexplored. Here, we identify by single-cell RNA sequencing and isolate a subset of vessel-associated cells able to improve myogenic differentiation. We termed them 'guide' cells because of their remarkable ability to improve myogenesis without fusing with the newly formed fibers. In vitro, these cells showed a marked mobility and ability to contact the forming myotubes. We found that these cells are characterized by CD44 and CD34 surface markers and the expression of Ng2 and Ncam2. In addition, in a murine model of acute muscle injury and regeneration, injection of guide cells correlated with increased numbers of newly formed neuromuscular junctions. Thus, we propose that guide cells modulate de novo generation of neuromuscular junctions in regenerating myofibers. Further studies are necessary to investigate the origin of those cells and the extent to which they are required for terminal specification of regenerating myofibers.
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27
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Carresi C, Scicchitano M, Scarano F, Macrì R, Bosco F, Nucera S, Ruga S, Zito MC, Mollace R, Guarnieri L, Coppoletta AR, Gliozzi M, Musolino V, Maiuolo J, Palma E, Mollace V. The Potential Properties of Natural Compounds in Cardiac Stem Cell Activation: Their Role in Myocardial Regeneration. Nutrients 2021; 13:275. [PMID: 33477916 PMCID: PMC7833367 DOI: 10.3390/nu13010275] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2020] [Revised: 01/07/2021] [Accepted: 01/12/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular diseases (CVDs), which include congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, and many other cardiac disorders, cause about 30% of deaths globally; representing one of the main health problems worldwide. Among CVDs, ischemic heart diseases (IHDs) are one of the major causes of morbidity and mortality in the world. The onset of IHDs is essentially due to an unbalance between the metabolic demands of the myocardium and its supply of oxygen and nutrients, coupled with a low regenerative capacity of the heart, which leads to great cardiomyocyte (CM) loss; promoting heart failure (HF) and myocardial infarction (MI). To date, the first strategy recommended to avoid IHDs is prevention in order to reduce the underlying risk factors. In the management of IHDs, traditional therapeutic options are widely used to improve symptoms, attenuate adverse cardiac remodeling, and reduce early mortality rate. However, there are no available treatments that aim to improve cardiac performance by replacing the irreversible damaged cardiomyocytes (CMs). Currently, heart transplantation is the only treatment being carried out for irreversibly damaged CMs. Hence, the discovery of new therapeutic options seems to be necessary. Interestingly, recent experimental evidence suggests that regenerative stem cell medicine could be a useful therapeutic approach to counteract cardiac damage and promote tissue regeneration. To this end, researchers are tasked with answering one main question: how can myocardial regeneration be stimulated? In this regard, natural compounds from plant extracts seem to play a particularly promising role. The present review will summarize the recent advances in our knowledge of stem cell therapy in the management of CVDs; focusing on the main properties and potential mechanisms of natural compounds in stimulating and activating stem cells for myocardial regeneration.
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Affiliation(s)
- Cristina Carresi
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Miriam Scicchitano
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Federica Scarano
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Roberta Macrì
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Francesca Bosco
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Saverio Nucera
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Stefano Ruga
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Maria Caterina Zito
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Rocco Mollace
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Lorenza Guarnieri
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Anna Rita Coppoletta
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Micaela Gliozzi
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Vincenzo Musolino
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Jessica Maiuolo
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
| | - Ernesto Palma
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
| | - Vincenzo Mollace
- Institute of Research for Food Safety & Health IRC-FSH, University Magna Graecia, 88100 Catanzaro, Italy; (F.S.); (R.M.); (F.B.); (S.N.); (S.R.); (M.C.Z.); (R.M.); (L.G.); (A.R.C.); (M.G.); (V.M.); (J.M.); (E.P.); (V.M.)
- Nutramed S.c.a.r.l., Complesso Ninì Barbieri, Roccelletta di Borgia, 88100 Catanzaro, Italy
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28
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Sridharan D, Palaniappan A, Blackstone BN, Dougherty JA, Kumar N, Seshagiri PB, Sayed N, Powell HM, Khan M. In situ differentiation of human-induced pluripotent stem cells into functional cardiomyocytes on a coaxial PCL-gelatin nanofibrous scaffold. MATERIALS SCIENCE & ENGINEERING. C, MATERIALS FOR BIOLOGICAL APPLICATIONS 2021; 118:111354. [PMID: 33254974 PMCID: PMC7708677 DOI: 10.1016/j.msec.2020.111354] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2020] [Revised: 08/03/2020] [Accepted: 08/05/2020] [Indexed: 12/20/2022]
Abstract
Human-induced pluripotent stem cells (hiPSCs) derived cardiomyocytes (hiPSC-CMs) have been explored for cardiac regeneration and repair as well as for the development of in vitro 3D cardiac tissue models. Existing protocols for cardiac differentiation of hiPSCs utilize a 2D culture system. However, the efficiency of hiPSC differentiation to cardiomyocytes in 3D culture systems has not been extensively explored. In the present study, we investigated the efficiency of cardiac differentiation of hiPSCs to functional cardiomyocytes on 3D nanofibrous scaffolds. Coaxial polycaprolactone (PCL)-gelatin fibrous scaffolds were fabricated by electrospinning and characterized using scanning electron microscopy (SEM) and fourier transform infrared (FTIR) spectroscopy. hiPSCs were cultured and differentiated into functional cardiomyocytes on the nanofibrous scaffold and compared with 2D cultures. To assess the relative efficiencies of both the systems, SEM, immunofluorescence staining and gene expression analyses were performed. Contractions of differentiated cardiomyocytes were observed in 2D cultures after 2 weeks and in 3D cultures after 4 weeks. SEM analysis showed no significant differences in the morphology of cells differentiated on 2D versus 3D cultures. However, gene expression data showed significantly increased expression of cardiac progenitor genes (ISL-1, SIRPA) in 3D cultures and cardiomyocytes markers (TNNT, MHC6) in 2D cultures. In contrast, immunofluorescence staining showed no substantial differences in the expression of NKX-2.5 and α-sarcomeric actinin. Furthermore, uniform migration and distribution of the in situ differentiated cardiomyocytes was observed in the 3D fibrous scaffold. Overall, our study demonstrates that coaxial PCL-gelatin nanofibrous scaffolds can be used as a 3D culture platform for efficient differentiation of hiPSCs to functional cardiomyocytes.
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Affiliation(s)
- Divya Sridharan
- Department of Emergency Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Arunkumar Palaniappan
- Department of Emergency Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA; Centre for Biomaterials, Cellular and Molecular Theranostics, Vellore Institute of Technology, Vellore, India
| | - Britani N Blackstone
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA
| | - Julie A Dougherty
- Department of Emergency Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH, USA
| | - Naresh Kumar
- Department of Microbial Infection and Immunity, The Ohio State University, Columbus, OH, USA
| | - Polani B Seshagiri
- Department of Molecular Reproduction Development and Genetics, Indian Institute of Science, C V Raman Road, Bangalore KA-560012, India
| | - Nazish Sayed
- Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA, USA
| | - Heather M Powell
- Department of Materials Science and Engineering, The Ohio State University, Columbus, OH, USA; Department of Biomedical Engineering, The Ohio State University, Columbus, OH, USA; Research Department, Shriners Hospitals for Children, Cincinnati, OH, USA
| | - Mahmood Khan
- Department of Emergency Medicine, Wexner Medical Center, The Ohio State University, Columbus, OH, USA; Department of Physiology and Cell Biology, Wexner Medical Center, The Ohio State University, Columbus, OH, USA; Dorothy M. Davis Heart & Lung Research Institute, Wexner Medical Center, The Ohio State University, Columbus, OH, USA.
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Berezin AE, Berezin AA. Stem-Cell-Based Cardiac Regeneration: Is There a Place For Optimism in the Future? Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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Galow AM, Goldammer T, Hoeflich A. Xenogeneic and Stem Cell-Based Therapy for Cardiovascular Diseases: Genetic Engineering of Porcine Cells and Their Applications in Heart Regeneration. Int J Mol Sci 2020; 21:ijms21249686. [PMID: 33353186 PMCID: PMC7766969 DOI: 10.3390/ijms21249686] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/11/2020] [Accepted: 12/15/2020] [Indexed: 12/25/2022] Open
Abstract
Cardiovascular diseases represent a major health concern worldwide with few therapy options for ischemic injuries due to the limited regeneration potential of affected cardiomyocytes. Innovative cell replacement approaches could facilitate efficient regenerative therapy. However, despite extensive attempts to expand primary human cells in vitro, present technological limitations and the lack of human donors have so far prevented their broad clinical use. Cell xenotransplantation might provide an ethically acceptable unlimited source for cell replacement therapies and bridge the gap between waiting recipients and available donors. Pigs are considered the most suitable candidates as a source for xenogeneic cells and tissues due to their anatomical and physiological similarities with humans. The potential of porcine cells in the field of stem cell-based therapy and regenerative medicine is under intensive investigation. This review outlines the current progress and highlights the most promising approaches in xenogeneic cell therapy with a focus on the cardiovascular system.
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Affiliation(s)
- Anne-Marie Galow
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany; (T.G.); (A.H.)
- Correspondence: ; Tel.: +49-38208-68-723
| | - Tom Goldammer
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany; (T.G.); (A.H.)
- Molecular Biology and Fish Genetics Unit, Faculty of Agriculture and Environmental Sciences, University of Rostock, 18059 Rostock, Germany
| | - Andreas Hoeflich
- Institute of Genome Biology, Leibniz Institute for Farm Animal Biology, 18196 Dummerstorf, Germany; (T.G.); (A.H.)
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Modak M, Frey MA, Yi S, Liu Y, Scott EA. Employment of targeted nanoparticles for imaging of cellular processes in cardiovascular disease. Curr Opin Biotechnol 2020; 66:59-68. [PMID: 32682272 PMCID: PMC7744313 DOI: 10.1016/j.copbio.2020.06.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 05/13/2020] [Accepted: 06/07/2020] [Indexed: 12/18/2022]
Abstract
Cardiovascular disease (CVD) is a leading cause of global mortality, accounting for pathologies that are primarily of atherosclerotic origin and driven by specific cell populations. A need exists for effective, non-invasive methods to assess the risk of potentially fatal major adverse cardiovascular events (MACE) before occurrence and to monitor post-interventional outcomes such as tissue regeneration. Molecular imaging has widespread applications in CVD diagnostic assessment, through modalities including magnetic resonance imaging (MRI), positron emission tomography (PET), and acoustic imaging methods. However, current gold-standard small molecule contrast agents are not cell-specific, relying on non-specific uptake to facilitate imaging of biologic processes. Nanomaterials can be engineered for targeted delivery to specific cell populations, and several nanomaterial systems have been developed for pre-clinical molecular imaging. Here, we review recent advances in nanoparticle-mediated approaches for imaging of cellular processes in cardiovascular disease, focusing on efforts to detect inflammation, assess lipid accumulation, and monitor tissue regeneration.
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Affiliation(s)
- Mallika Modak
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA
| | - Molly A Frey
- Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA; Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA
| | - Sijia Yi
- Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA
| | - Yugang Liu
- Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA
| | - Evan A Scott
- Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA; Interdisciplinary Biological Sciences, Northwestern University, Evanston, IL, USA; Chemistry of Life Processes Institute, Northwestern University, Evanston, IL 60208, USA; Department of Microbiology-Immunology, Northwestern University, Chicago, IL 60611, USA; Simpson Querrey Institute, Northwestern University, Chicago, IL 60611, USA.
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Peng SY, Wu TH, Lin TY, Hii LY, Chan KS, Fu TY, Chang SC, Shen PC, Liu KY, Shaw SW. Application of cattle placental stem cells for treating ovarian follicular cyst. World J Stem Cells 2020; 12:1366-1376. [PMID: 33312404 PMCID: PMC7705470 DOI: 10.4252/wjsc.v12.i11.1366] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2020] [Revised: 07/02/2020] [Accepted: 09/08/2020] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND High humidity and temperature in Taiwan have significant effects on the reproductivity of Holstein cattle, resulting in the occurrence of bovine ovarian follicular cyst (OFC). Because of economic loss from OFC, manual rupture and hormone injection have been advocated for the management of OFC. However, these incomplete treatments increase hormone resistance in cattle. Mesenchymal stem cells (MSCs) derived from placental stem cells (PSCs) demonstrate potential properties for the treatment of several diseases via promoting angiogenesis and immune modulation.
AIM To establish the possibility of cattle placental stem cells (CPSCs) as a treatment modality for OFC of cows in Taiwan.
METHODS The cows with OFC were divided into three groups: control (BC1 and BC2), hormone (H1 and H2), and CPSC (PS1 and PS2) treatment groups. In the hormone treatment group, the cows were given gonadotrophin-releasing hormone (GnRH)-prostaglandin-GnRH intramuscular injection with or without drainage of follicular fluid. In the CPSC treatment group, CPSCs were isolated from the placenta after labor. With the identification of surface antigen on stem cells, the cows were administered ovarian injection of 1 × 106 or 6 × 106 CPSCs with drainage. In all groups, OFC was scanned by ultrasound once a week for a total of seven times. The concentrations of estradiol and progesterone in serum were tested in the same period. The estrus cycle was analyzed by food intake and activity. If estrus was detected, artificial insemination was conducted. Then the cow was monitored by ultrasound for confirmation of pregnancy.
RESULTS After 7 d of culture, CPSCs were successfully isolated from placental pieces. CPSCs significantly proliferated every 24 h and had high expression of MSC markers such as cluster of differentiation 44, as determined by flow cytometry. Ultrasound showed lower numbers of OFCs with drainage of follicular fluid. We achieved recovery rates of 0%, 50%, 50%, 75%, 75% and 75% in BC1, BC2, H1, H2, PS1, and PS2, respectively. Higher concentrations of progesterone were detected in the CPSC treatment groups. However, both hormone and CPSC treatment groups had no significant difference in the concentration of estradiol. The estrus rate was 0%, 100%, 25%, 75%, 75% and 75% in BC1, BC2, H1, H2, PS1, and PS2, respectively. The two fetuses were born in H2 and PS1. In brief, cows with CPSC injection achieved higher recovery, estrus, and inseminated conception rates.
CONCLUSION CPSCs have efficacy in treating cows with OFC, and thus, may serve as an alternative treatment for reproductive disorders.
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Affiliation(s)
- Shao-Yu Peng
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Tsung-Hsin Wu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Tzu-Yi Lin
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
| | - Ling-Yien Hii
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Kok-Seong Chan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
| | - Tzu-Yen Fu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Shen-Chang Chang
- Kaohsiung Animal Propagation Station, Livestock Research Institute, Council of Agriculture, Executive Yuan, Pingtung 912, Taiwan
| | - Perng-Chih Shen
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Kang-You Liu
- Department of Animal Science, National Pingtung University of Science and Technology, Pingtung 912, Taiwan
| | - Steven W. Shaw
- College of Medicine, Chang Gung University, Taoyuan 333, Taiwan
- Department of Obstetrics and Gynecology, Taipei Chang Gung Memorial Hospital, Taipei 105, Taiwan
- Prenatal Cell and Gene Therapy Group, Institute for Women's Health, University College London, London WC1E 6HU, United Kingdom
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Kook YM, Hwang S, Kim H, Rhee KJ, Lee K, Koh WG. Cardiovascular tissue regeneration system based on multiscale scaffolds comprising double-layered hydrogels and fibers. Sci Rep 2020; 10:20321. [PMID: 33230134 PMCID: PMC7683622 DOI: 10.1038/s41598-020-77187-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2020] [Accepted: 11/04/2020] [Indexed: 12/16/2022] Open
Abstract
We report a technique to reconstruct cardiovascular tissue using multiscale scaffolds incorporating polycaprolactone fibers with double-layered hydrogels comprising fibrin hydrogel surrounded by secondary alginate hydrogel. The scaffolds compartmentalized cells into the core region of cardiac tissue and the peripheral region of blood vessels to construct cardiovascular tissue, which was accomplished by a triple culture system of adipose-derived mesenchymal stem cells (ADSCs) with C2C12 myoblasts on polycaprolactone (PCL) fibers along with human umbilical vein endothelial cells (HUVECs) in fibrin hydrogel. The secondary alginate hydrogel prevented encapsulated cells from migrating outside scaffold and maintained the scaffold structure without distortion after subcutaneous implantation. According to in vitro studies, resultant scaffolds promoted new blood vessel formation as well as cardiomyogenic phenotype expression of ADSCs. Cardiac muscle-specific genes were expressed from stem cells and peripheral blood vessels from HUVECs were also successfully developed in subcutaneously implanted cell-laden multiscale scaffolds. Furthermore, the encapsulated stem cells modulated the immune response of scaffolds by secreting anti-inflammatory cytokines for successful tissue construction. Our study reveals that multiscale scaffolds can be promising for the remodeling and transplantation of cardiovascular tissue.
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Affiliation(s)
- Yun-Min Kook
- Department of Chemical and Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, Republic of Korea
| | - Soonjae Hwang
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju, Gangwon-do, 220-710, Republic of Korea.,Natural Product Informatics Research Center, Korea Institute of Science and Technology, Gangneung, Gangwon-do, 25451, Republic of Korea
| | - Hyerim Kim
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea
| | - Ki-Jong Rhee
- Department of Biomedical Laboratory Science, College of Health Sciences, Yonsei University at Wonju, Wonju, Gangwon-do, 220-710, Republic of Korea
| | - Kangwon Lee
- Program in Nanoscience and Technology, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, Republic of Korea. .,Advanced Institutes of Convergence Technology, Suwon, Gyeonggi-do, Republic of Korea.
| | - Won-Gun Koh
- Department of Chemical and Biomolecular Engineering, Yonsei University, 50 Yonsei-ro, Seodaemun-gu, Seoul, 120-749, Republic of Korea.
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De Bleye C, Fontaine M, Dumont E, Sacré PY, Hubert P, Theys N, Ziemons E. Raman imaging as a new analytical tool for the quality control of the monitoring of osteogenic differentiation in forming 3D bone tissue. J Pharm Biomed Anal 2020; 186:113319. [PMID: 32361470 DOI: 10.1016/j.jpba.2020.113319] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2019] [Revised: 04/09/2020] [Accepted: 04/15/2020] [Indexed: 12/20/2022]
Abstract
In this study, adipose-derived stem cells (ASCs) are used to produce 3D bone grafts. The safety and the feasibility of using these bone grafts have been already showed and quality controls are already implemented. However, a cheaper, fast and non-destructive technique is required to monitor the osteogenic differentiation process. Here, the use of Raman imaging to monitor the synthesis of the extracellular matrix and its progressive mineralization occurring during the osteogenic differentiation process is investigated for the first time on a 3D in forming bone tissue. The attention was focused on Raman bands related to this matrix belonging to phosphate, phenylalanine and hydroxyproline, which are very distinctive and intense. The kinetic of the osteogenic differentiation process was first compared between a 2D and a 3D forming bone tissue. It was observed that the kinetics of the osteogenic differentiation process is slower in 3D in forming bone tissue. In a second step, an evaluation of the reliability of the Raman imaging method was performed including a study of the influence of the harvest biopsies position on the forming 3D bone tissue. The repeatability and the specificity of this method were also demonstrated. In a last step, several batches of ASCs were cultured and analyzed in 3D at different time points using Raman imaging. From the mean Raman spectra, mineral to matrix ratios (MTMR) were determined and used to evaluate the formation of mineral deposits accompanying the extracellular matrix synthesis which is indicative of an ongoing osteogenic differentiation process. These ratios peaked between the day 35 and 49. This observation was very interesting since it corresponds to the time at which the 3D bone grafts are used for the patient surgery. To conclude, Raman imaging allowed fast acquisition and time-resolved monitoring in vitro of the mineralization of extracellular matrix during osteogenic differentiation.
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Affiliation(s)
- C De Bleye
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium.
| | - M Fontaine
- Novadip Biosciences, Rue Grandbonpré 11, 1435 Mont-Saint-Guibert, Belgium
| | - E Dumont
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
| | - P-Y Sacré
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
| | - Ph Hubert
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
| | - N Theys
- Novadip Biosciences, Rue Grandbonpré 11, 1435 Mont-Saint-Guibert, Belgium
| | - E Ziemons
- University of Liege (ULiege), CIRM, Vibra-Santé HUB, Department of Pharmacy, Laboratory of Pharmaceutical Analytical Chemistry, CHU, Avenue Hippocrate 15, B36, 4000 Liège, Belgium
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Liu Z, Wu C, Zou X, Shen W, Yang J, Zhang X, Hu X, Wang H, Liao Y, Jing T. Exosomes derived from mesenchymal stem cells inhibit neointimal hyperplasia by activating the Erk1/2 signalling pathway in rats. Stem Cell Res Ther 2020; 11:220. [PMID: 32513275 PMCID: PMC7278178 DOI: 10.1186/s13287-020-01676-w] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2019] [Revised: 03/17/2020] [Accepted: 04/13/2020] [Indexed: 01/29/2023] Open
Abstract
Background Restenosis is a serious problem in patients who have undergone percutaneous transluminal angioplasty. Endothelial injury resulting from surgery can lead to endothelial dysfunction and neointimal formation by inducing aberrant proliferation and migration of vascular smooth muscle cells. Exosomes secreted by mesenchymal stem cells have been a hot topic in cardioprotective research. However, to date, exosomes derived from mesenchymal stem cells (MSC-Exo) have rarely been reported in association with restenosis after artery injury. The aim of this study was to investigate whether MSC-Exo inhibit neointimal hyperplasia in a rat model of carotid artery balloon-induced injury and, if so, to explore the underlying mechanisms. Methods Characterization of MSC-Exo immunophenotypes was performed by electron microscopy, nanoparticle tracking analysis and western blot assays. To investigate whether MSC-Exo inhibited neointimal hyperplasia, rats were intravenously injected with normal saline or MSC-Exo after carotid artery balloon-induced injury. Haematoxylin-eosin staining was performed to examine the intimal and media areas. Evans blue dye staining was performed to examine re-endothelialization. Moreover, immunohistochemistry and immunofluorescence were performed to examine the expression of CD31, vWF and α-SMA. To further investigate the involvement of MSC-Exo-induced re-endothelialization, the underlying mechanisms were studied by cell counting kit-8, cell scratch, immunofluorescence and western blot assays. Results Our data showed that MSC-Exo were ingested by endothelial cells and that systemic injection of MSC-Exo suppressed neointimal hyperplasia after artery injury. The Evans blue staining results showed that MSC-Exo could accelerate re-endothelialization compared to the saline group. The immunofluorescence and immunohistochemistry results showed that MSC-Exo upregulated the expression of CD31 and vWF but downregulated the expression of α-SMA. Furthermore, MSC-Exo mechanistically facilitated proliferation and migration by activating the Erk1/2 signalling pathway. The western blot results showed that MSC-Exo upregulated the expression of PCNA, Cyclin D1, Vimentin, MMP2 and MMP9 compared to that in the control group. Interestingly, an Erk1/2 inhibitor reversed the expression of the above proteins. Conclusion Our data suggest that MSC-Exo can inhibit neointimal hyperplasia after carotid artery injury by accelerating re-endothelialization, which is accompanied by activation of the Erk1/2 signalling pathway. Importantly, our study provides a novel cell-free approach for the treatment of restenosis diseases after intervention.
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Affiliation(s)
- Zhihui Liu
- Department of Cardiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.,State Key Laboratory of Silkworm Genome Biology, The Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China
| | - Chao Wu
- State Key Laboratory of Silkworm Genome Biology, The Institute of Sericulture and Systems Biology, Southwest University, Chongqing, China.,Department of Thoracic Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xinliang Zou
- Department of Cardiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China
| | - Weiming Shen
- Laboratory of Integrative Medicine, School of Basic Medical Sciences, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Jiacai Yang
- The Institute of Burn Research, South-West Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaorong Zhang
- The Institute of Burn Research, South-West Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaohong Hu
- The Institute of Burn Research, South-West Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Haidong Wang
- Department of Thoracic Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Yi Liao
- Department of Thoracic Surgery, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Tao Jing
- Department of Cardiology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, 400038, China.
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Wasserman AH, Venkatesan M, Aguirre A. Bioactive Lipid Signaling in Cardiovascular Disease, Development, and Regeneration. Cells 2020; 9:E1391. [PMID: 32503253 PMCID: PMC7349721 DOI: 10.3390/cells9061391] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Revised: 05/23/2020] [Accepted: 06/01/2020] [Indexed: 12/13/2022] Open
Abstract
Cardiovascular disease (CVD) remains a leading cause of death globally. Understanding and characterizing the biochemical context of the cardiovascular system in health and disease is a necessary preliminary step for developing novel therapeutic strategies aimed at restoring cardiovascular function. Bioactive lipids are a class of dietary-dependent, chemically heterogeneous lipids with potent biological signaling functions. They have been intensively studied for their roles in immunity, inflammation, and reproduction, among others. Recent advances in liquid chromatography-mass spectrometry techniques have revealed a staggering number of novel bioactive lipids, most of them unknown or very poorly characterized in a biological context. Some of these new bioactive lipids play important roles in cardiovascular biology, including development, inflammation, regeneration, stem cell differentiation, and regulation of cell proliferation. Identifying the lipid signaling pathways underlying these effects and uncovering their novel biological functions could pave the way for new therapeutic strategies aimed at CVD and cardiovascular regeneration.
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Affiliation(s)
- Aaron H. Wasserman
- Regenerative Biology and Cell Reprogramming Laboratory, Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI 48824, USA; (A.H.W.); (M.V.)
- Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Manigandan Venkatesan
- Regenerative Biology and Cell Reprogramming Laboratory, Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI 48824, USA; (A.H.W.); (M.V.)
- Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI 48824, USA
| | - Aitor Aguirre
- Regenerative Biology and Cell Reprogramming Laboratory, Institute for Quantitative Health Science and Engineering (IQ), Michigan State University, East Lansing, MI 48824, USA; (A.H.W.); (M.V.)
- Department of Biomedical Engineering, College of Engineering, Michigan State University, East Lansing, MI 48824, USA
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Turner D, Rieger AC, Balkan W, Hare JM. Clinical-based Cell Therapies for Heart Disease-Current and Future State. Rambam Maimonides Med J 2020; 11:RMMJ.10401. [PMID: 32374254 PMCID: PMC7202446 DOI: 10.5041/rmmj.10401] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Patients have an ongoing unmet need for effective therapies that reverse the cellular and functional damage associated with heart damage and disease. The discovery that ~1%-2% of adult cardiomyocytes turn over per year provided the impetus for treatments that stimulate endogenous repair mechanisms that augment this rate. Preclinical and clinical studies provide evidence that cell-based therapy meets these therapeutic criteria. Recent and ongoing studies are focused on determining which cell type(s) works best for specific patient population(s) and the mechanism(s) by which these cells promote repair. Here we review clinical and preclinical stem cell studies and anticipate future directions of regenerative medicine for heart disease.
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Affiliation(s)
- Darren Turner
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Angela C. Rieger
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Wayne Balkan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
| | - Joshua M. Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida, USA
- Department of Medicine, University of Miami Miller School of Medicine, Miami, Florida, USA
- To whom correspondence should be addressed. E-mail:
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Huang K, Ozpinar EW, Su T, Tang J, Shen D, Qiao L, Hu S, Li Z, Liang H, Mathews K, Scharf V, Freytes DO, Cheng K. An off-the-shelf artificial cardiac patch improves cardiac repair after myocardial infarction in rats and pigs. Sci Transl Med 2020; 12:eaat9683. [PMID: 32269164 PMCID: PMC7293901 DOI: 10.1126/scitranslmed.aat9683] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2018] [Revised: 02/26/2019] [Accepted: 03/03/2020] [Indexed: 12/12/2022]
Abstract
Cell therapy has been a promising strategy for cardiac repair after injury or infarction; however, low retention and engraftment of transplanted cells limit potential therapeutic efficacy. Seeding scaffold material with cells to create cardiac patches that are transplanted onto the surface of the heart can overcome these limitations. However, because patches need to be freshly prepared to maintain cell viability, long-term storage is not feasible and limits clinical applicability. Here, we developed an off-the-shelf therapeutic cardiac patch composed of a decellularized porcine myocardial extracellular matrix scaffold and synthetic cardiac stromal cells (synCSCs) generated by encapsulating secreted factors from isolated human cardiac stromal cells. This fully acellular artificial cardiac patch (artCP) maintained its potency after long-term cryopreservation. In a rat model of acute myocardial infarction, transplantation of the artCP supported cardiac recovery by reducing scarring, promoting angiomyogenesis, and boosting cardiac function. The safety and efficacy of the artCP were further confirmed in a porcine model of myocardial infarction. The artCP is a clinically feasible, easy-to-store, and cell-free alternative to myocardial repair using cell-based cardiac patches.
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Affiliation(s)
- Ke Huang
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
| | - Emily W Ozpinar
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Teng Su
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Junnan Tang
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
| | - Deliang Shen
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
| | - Li Qiao
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
| | - Shiqi Hu
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Zhenhua Li
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Hongxia Liang
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA
| | - Kyle Mathews
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27607, USA
| | - Valery Scharf
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27607, USA
| | - Donald O Freytes
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences, North Carolina State University, Raleigh, NC 27607, USA.
- Comparative Medicine Institute, North Carolina State University, Raleigh, NC 27607, USA
- Department of Clinical Sciences, North Carolina State University, Raleigh, NC 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC 27607, USA
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Jang WB, Ji ST, Park JH, Kim YJ, Kang S, Kim DY, Lee NK, Kim JS, Lim HJ, Choi J, Le THV, Ly TTG, Rethineswaran VK, Kim DH, Ha JS, Yun J, Baek SH, Kwon SM. Engineered M13 Peptide Carrier Promotes Angiogenic Potential of Patient-Derived Human Cardiac Progenitor Cells and In Vivo Engraftment. Tissue Eng Regen Med 2020; 17:323-333. [PMID: 32227286 DOI: 10.1007/s13770-020-00244-w] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2019] [Revised: 01/19/2020] [Accepted: 02/06/2020] [Indexed: 12/28/2022] Open
Abstract
BACKGROUND Despite promising advances in stem cell-based therapy, the treatment of ischemic cardiovascular diseases remains a big challenge due to both the insufficient in vivo viability of transplanted cells and poor angiogenic potential of stem cells. The goal of this study was to develop therapeutic human cardiac progenitor cells (hCPCs) for ischemic cardiovascular diseases with a novel M13 peptide carrier. METHOD In this study, an engineered M13 peptide carrier was successfully generated using a QuikChange Kit. The cellular function of M13 peptide carrier-treated hCPCs was assessed using a tube formation assay and scratch wound healing assay. The in vivo engraftment and cell survival bioactivities of transplanted cells were demonstrated by immunohistochemistry after hCPC transplantation into a myocardial infarction animal model. RESULTS The engineered M13RGD+SDKP peptide carrier, which expressed RGD peptide on PIII site and SDKP peptide on PVIII site, did not affect morphologic change and proliferation ability in hCPCs. In contrast, hCPCs treated with M13RGD+SDKP showed enhanced angiogenic capacity, including tube formation and migration capacity. Moreover, transplanted hCPCs with M13RGD+SDKP were engrafted into the ischemic region and promoted in vivo cell survival. CONCLUSION Our present data provides a promising protocol for CPC-based cell therapy via short-term cell priming of hCPCs with engineered M13RGD+SDKP before cell transplantation for treatment of cardiovascular disease.
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Affiliation(s)
- Woong Bi Jang
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Seung Taek Ji
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Ji Hye Park
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Yeon-Ju Kim
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Songhwa Kang
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Da Yeon Kim
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Na-Kyung Lee
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Jin Su Kim
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Hye Ji Lim
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Jaewoo Choi
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Thi Hong Van Le
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Thanh Truong Giang Ly
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Vinoth Kumar Rethineswaran
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Dong Hwan Kim
- Department of Neurosurgery & Medical Research Institute, Pusan National University Hospital, 179 Gudeok-ro, Seo-gu, Busan, 49241, Republic of Korea
| | - Jong Seong Ha
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Jisoo Yun
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea
| | - Sang Hong Baek
- Division of Cardiology, Seoul St. Mary's Hospital, School of Medicine, the Catholic University of Korea, 505, Banpo-dong, Seocho-gu, Seoul, 06591, Republic of Korea.
| | - Sang-Mo Kwon
- Laboratory of Regenerative Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea. .,Research Institute of Convergence Biomedical Science and Technology, Pusan National University School of Medicine, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea. .,Laboratory for Vascular Medicine and Stem Cell Biology, Department of Physiology, Medical Research Institute, School of Medicine, Pusan National University, 20 Geumo-ro, Mulgeum-eup, Yangsan, 50612, Republic of Korea.
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Lou X, Zhao M, Fan C, Fast VG, Valarmathi MT, Zhu W, Zhang J. N-cadherin overexpression enhances the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes in infarcted mouse hearts. Cardiovasc Res 2020; 116:671-685. [PMID: 31350544 DOI: 10.1093/cvr/cvz179] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2018] [Revised: 03/29/2019] [Accepted: 07/19/2019] [Indexed: 12/30/2022] Open
Abstract
AIMS In regenerative medicine, cellular cardiomyoplasty is one of the promising options for treating myocardial infarction (MI); however, the efficacy of such treatment has shown to be limited due to poor survival and/or functional integration of implanted cells. Within the heart, the adhesion between cardiac myocytes (CMs) is mediated by N-cadherin (CDH2) and is critical for the heart to function as an electromechanical syncytium. In this study, we have investigated whether the reparative potency of human-induced pluripotent stem cell-derived cardiac myocytes (hiPSC-CMs) can be enhanced through CDH2 overexpression. METHODS AND RESULTS CDH2-hiPSC-CMs and control wild-type (WT)-hiPSC-CMs were cultured in myogenic differentiation medium for 28 days. Using a mouse MI model, the cell survival/engraftment rate, infarct size, and cardiac functions were evaluated post-MI, at Day 7 or Day 28. In vitro, conduction velocities were significantly greater in CDH2-hiPSC-CMs than in WT-hiPSC-CMs. While, in vivo, measurements of cardiac functions: left ventricular (LV) ejection fraction, reduction in infarct size, and the cell engraftment rate were significantly higher in CDH2-hiPSC-CMs treated MI group than in WT-hiPSC-CMs treated MI group. Mechanistically, paracrine activation of ERK signal transduction pathway by CDH2-hiPSC-CMs, significantly induced neo-vasculogenesis, resulting in a higher survival of implanted cells. CONCLUSION Collectively, these data suggest that CDH2 overexpression enhances not only the survival/engraftment of cultured CDH2-hiPSC-CMs, but also the functional integration of these cells, consequently, the augmentation of the reparative properties of implanted CDH2-hiPSC-CMs in the failing hearts.
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Affiliation(s)
- Xi Lou
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
| | - Meng Zhao
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
| | - Chengming Fan
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
| | - Vladimir G Fast
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
| | - Mani T Valarmathi
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
| | - Wuqiang Zhu
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
| | - Jianyi Zhang
- Department of Biomedical Engineering, School of Medicine and School of Engineering, University of Alabama at Birmingham, 1670 University Boulevard, Volker Hall G094J, Birmingham, AL 35294, USA
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Sinnappah-Kang N, Mathen C. Stem cell research and therapy in India: General awareness for the public and stem cell therapy providers. CHRISMED JOURNAL OF HEALTH AND RESEARCH 2020. [DOI: 10.4103/cjhr.cjhr_91_19] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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Grigorian Shamagian L, Madonna R, Taylor D, Climent AM, Prosper F, Bras-Rosario L, Bayes-Genis A, Ferdinandy P, Fernández-Avilés F, Izpisua Belmonte JC, Fuster V, Bolli R. Perspectives on Directions and Priorities for Future Preclinical Studies in Regenerative Medicine. Circ Res 2019; 124:938-951. [PMID: 30870121 DOI: 10.1161/circresaha.118.313795] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
The myocardium consists of numerous cell types embedded in organized layers of ECM (extracellular matrix) and requires an intricate network of blood and lymphatic vessels and nerves to provide nutrients and electrical coupling to the cells. Although much of the focus has been on cardiomyocytes, these cells make up <40% of cells within a healthy adult heart. Therefore, repairing or regenerating cardiac tissue by merely reconstituting cardiomyocytes is a simplistic and ineffective approach. In fact, when an injury occurs, cardiac tissue organization is disrupted at the level of the cells, the tissue architecture, and the coordinated interaction among the cells. Thus, reconstitution of a functional tissue must reestablish electrical and mechanical communication between cardiomyocytes and restore their surrounding environment. It is also essential to restore distinctive myocardial features, such as vascular patency and pump function. In this article, we review the current status, challenges, and future priorities in cardiac regenerative or reparative medicine. In the first part, we provide an overview of our current understanding of heart repair and comment on the main contributors and mechanisms involved in innate regeneration. A brief section is dedicated to the novel concept of rejuvenation or regeneration, which we think may impact future development in the field. The last section describes regenerative therapies, where the most advanced and disruptive strategies used for myocardial repair are discussed. Our recommendations for priority areas in studies of cardiac regeneration or repair are summarized in Tables 1 and 2 .
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Affiliation(s)
- Lilian Grigorian Shamagian
- From the Hospital Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (L.G.S., A.M.C., F.F.-A.).,CIBERCV, ISCIII, Madrid, Spain (L.G.S., A.M.C., A.B.-G., F.F.-A., V.F.)
| | - Rosalinda Madonna
- Center of Aging Sciences and Translational Medicine (CESI-MeT), Institute of Cardiology, G. d'Annunzio University, Chieti, Italy (R.M.).,Department of Internal Medicine, the University of Texas Health Science Center at Houston (R.M., )
| | | | - Andreu M Climent
- From the Hospital Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (L.G.S., A.M.C., F.F.-A.).,CIBERCV, ISCIII, Madrid, Spain (L.G.S., A.M.C., A.B.-G., F.F.-A., V.F.)
| | | | - Luis Bras-Rosario
- Cardiology Department, Santa Maria University Hospital (CHLN), Lisbon Academic Medical Centre and Cardiovascular Centre of the University of Lisbon, Faculty of Medicine, Portugal (L.B.-R.)
| | - Antoni Bayes-Genis
- CIBERCV, ISCIII, Madrid, Spain (L.G.S., A.M.C., A.B.-G., F.F.-A., V.F.).,Hospital Germans Trias i Pujol, Badalona, Spain (A.B.-G.)
| | - Péter Ferdinandy
- Department of Pharmacology and Pharmacotherapy, Semmelweis University, Budapest, Hungary (P.F.).,Pharmahungary Group, Szeged, Hungary (P.F.)
| | - Francisco Fernández-Avilés
- From the Hospital Gregorio Marañón, Instituto de Investigación Sanitaria Gregorio Marañón, Universidad Complutense, Madrid, Spain (L.G.S., A.M.C., F.F.-A.).,CIBERCV, ISCIII, Madrid, Spain (L.G.S., A.M.C., A.B.-G., F.F.-A., V.F.)
| | | | - Valentin Fuster
- CIBERCV, ISCIII, Madrid, Spain (L.G.S., A.M.C., A.B.-G., F.F.-A., V.F.).,The Mount Sinai Hospital, New York, NY (V.F.).,Centro Nacional de Investigaciones Cardiovasculares Carlos III (CNIC), Madrid, Spain (V.F.)
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Carotenuto F, Teodori L, Maccari AM, Delbono L, Orlando G, Di Nardo P. Turning regenerative technologies into treatment to repair myocardial injuries. J Cell Mol Med 2019; 24:2704-2716. [PMID: 31568640 PMCID: PMC7077550 DOI: 10.1111/jcmm.14630] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2019] [Revised: 06/28/2019] [Accepted: 07/23/2019] [Indexed: 02/06/2023] Open
Abstract
Regenerative therapies including stem cell treatments hold promise to allow curing patients affected by severe cardiac muscle diseases. However, the clinical efficacy of stem cell therapy remains elusive, so far. The two key roadblocks that still need to be overcome are the poor cell engraftment into the injured myocardium and the limited knowledge of the ideal mixture of bioactive factors to be locally delivered for restoring heart function. Thus, therapeutic strategies for cardiac repair are directed to increase the retention and functional integration of transplanted cells in the damaged myocardium or to enhance the endogenous repair mechanisms through cell‐free therapies. In this context, biomaterial‐based technologies and tissue engineering approaches have the potential to dramatically impact cardiac translational medicine. This review intends to offer some consideration on the cell‐based and cell‐free cardiac therapies, their limitations and the possible future developments.
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Affiliation(s)
- Felicia Carotenuto
- Centro Interdipartimentale di Medicina Rigenerativa, Università di Roma Tor Vergata, Rome, Italy.,Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy.,Diagnostics and Metrology (FSN-TECFIS-DIM), ENEA, C.R. Frascati, Rome, Italy
| | - Laura Teodori
- Diagnostics and Metrology (FSN-TECFIS-DIM), ENEA, C.R. Frascati, Rome, Italy
| | - Anna Maria Maccari
- Centro Interdipartimentale di Medicina Rigenerativa, Università di Roma Tor Vergata, Rome, Italy.,Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy
| | - Luciano Delbono
- Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Giuseppe Orlando
- Wake Forest University School of Medicine, Winston Salem, NC, USA.,Department of Surgery, Wake Forest University School of Medicine, Winston Salem, NC, USA
| | - Paolo Di Nardo
- Centro Interdipartimentale di Medicina Rigenerativa, Università di Roma Tor Vergata, Rome, Italy.,Dipartimento di Scienze Cliniche e Medicina Traslazionale, Università di Roma Tor Vergata, Rome, Italy.,I.M. Sechenov First Moscow State Medical University, Moscow, Russia
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Kim IG, Hwang MP, Park JS, Kim S, Kim J, Kang HJ, Subbiah R, Ko UH, Shin JH, Kim C, Choi D, Park K. Stretchable ECM Patch Enhances Stem Cell Delivery for Post-MI Cardiovascular Repair. Adv Healthc Mater 2019; 8:e1900593. [PMID: 31304685 DOI: 10.1002/adhm.201900593] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Indexed: 12/18/2022]
Abstract
Current cell-based therapies administered after myocardial infarction (MI) show limited efficacy due to subpar cell retention in a dynamically beating heart. In particular, cardiac patches generally provide a cursory level of cell attachment due to the lack of an adequate microenvironment. From this perspective, decellularized cell-derived ECM (CDM) is attractive in its recapitulation of a natural biophysical environment for cells. Unfortunately, its weak physical property renders it difficult to retain in its original form, limiting its full potential. Here, a novel strategy to peel CDM off from its underlying substrate is proposed. By physically stamping it onto a polyvinyl alcohol hydrogel, the resulting stretchable extracellular matrix (ECM) membrane preserves the natural microenvironment of CDM, thereby conferring a biological interface to a viscoelastic membrane. Its various mechanical and biological properties are characterized and its capacity to improve cardiomyocyte functionality is demonstrated. Finally, evidence of enhanced stem cell delivery using the stretchable ECM membrane is presented, which leads to improved cardiac remodeling in a rat MI model. A new class of material based on natural CDM is envisioned for the enhanced delivery of cells and growth factors that have a known affinity with ECM.
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Affiliation(s)
- In Gul Kim
- Center for BiomaterialsKorea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
- Department of Otorhinolaryngology‐Head and Neck SurgerySeoul National University Hospital Seoul 03080 Republic of Korea
| | - Mintai P. Hwang
- Center for BiomaterialsKorea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
- Meinig School of Biomedical EngineeringCornell University Ithaca NY 14853 USA
| | - Jin Sil Park
- Severance Cardiovascular HospitalYonsei University Health System Seoul 03722 Republic of Korea
| | - Su‐Hyun Kim
- Center for NeuroscienceKorea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
| | - Jung‐Hyun Kim
- Severance Cardiovascular HospitalYonsei University Health System Seoul 03722 Republic of Korea
| | - Hyo Jin Kang
- Severance Cardiovascular HospitalYonsei University Health System Seoul 03722 Republic of Korea
| | - Ramesh Subbiah
- Center for BiomaterialsKorea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
| | - Ung Hyun Ko
- Department of Mechanical EngineeringKorea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea
| | - Jennifer H. Shin
- Department of Mechanical EngineeringKorea Advanced Institute of Science and Technology (KAIST) Daejeon 34141 Republic of Korea
| | - Chong‐Hyun Kim
- Center for NeuroscienceKorea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
| | - Donghoon Choi
- Severance Cardiovascular HospitalYonsei University Health System Seoul 03722 Republic of Korea
| | - Kwideok Park
- Center for BiomaterialsKorea Institute of Science and Technology (KIST) Seoul 02792 Republic of Korea
- Division of Bio‐Medical Science and TechnologyUniversity of Science and Technology (UST) Seoul 02792 Republic of Korea
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Alonzo M, AnilKumar S, Roman B, Tasnim N, Joddar B. 3D Bioprinting of cardiac tissue and cardiac stem cell therapy. Transl Res 2019; 211:64-83. [PMID: 31078513 PMCID: PMC6702075 DOI: 10.1016/j.trsl.2019.04.004] [Citation(s) in RCA: 83] [Impact Index Per Article: 13.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/03/2019] [Revised: 04/01/2019] [Accepted: 04/03/2019] [Indexed: 12/17/2022]
Abstract
Cardiovascular tissue engineering endeavors to repair or regenerate damaged or ineffective blood vessels, heart valves, and cardiac muscle. Current strategies that aim to accomplish such a feat include the differentiation of multipotent or pluripotent stem cells on appropriately designed biomaterial scaffolds that promote the development of mature and functional cardiac tissue. The advent of additive manufacturing 3D bioprinting technology further advances the field by allowing heterogenous cell types, biomaterials, and signaling factors to be deposited in precisely organized geometries similar to those found in their native counterparts. Bioprinting techniques to fabricate cardiac tissue in vitro include extrusion, inkjet, laser-assisted, and stereolithography with bioinks that are either synthetic or naturally-derived. The article further discusses the current practices for postfabrication conditioning of 3D engineered constructs for effective tissue development and stability, then concludes with prospective points of interest for engineering cardiac tissues in vitro. Cardiovascular three-dimensional bioprinting has the potential to be translated into the clinical setting and can further serve to model and understand biological principles that are at the root of cardiovascular disease in the laboratory.
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Affiliation(s)
- Matthew Alonzo
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, Texas
| | - Shweta AnilKumar
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, Texas
| | - Brian Roman
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, Texas
| | - Nishat Tasnim
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, Texas
| | - Binata Joddar
- Inspired Materials & Stem-Cell Based Tissue Engineering Laboratory (IMSTEL), Department of Metallurgical, Materials and Biomedical Engineering, University of Texas at El Paso, El Paso, Texas; Border Biomedical Research Center, University of Texas at El Paso, El Paso, Texas.
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Cai X, Zhu Z, Zhang Y, Tian X. SDF-1α promotes repair of myocardial ischemic necrosis zones in rats. INTERNATIONAL JOURNAL OF CLINICAL AND EXPERIMENTAL PATHOLOGY 2019; 12:1956-1967. [PMID: 31934018 PMCID: PMC6949651] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 02/28/2019] [Accepted: 04/19/2019] [Indexed: 06/10/2023]
Abstract
OBJECTIVE To explore the repair effect of stromal cell-derived factor-1α (SDF-1α) on myocardial ischemic necrosis zones. METHODS Lentivirus (LV-SDF-1α-GFP) containing SDF-1α target gene was established, the separated and cultured neonatal rat cardiac fibroblasts were transfected, and caudal intravenous injection of isoproterenol was conducted to prepare a rat model of myocardial ischemia. Small animal ultrasound was used to evaluate the effect on cardiac functions. Morphology and immunofluorescence were used to observe the change of ischemic necrosis zones and expressions of stem cellular markers c-kit, CD34, nkx2.5, and nanog, and a quantitative analysis was performed. RESULTS The established LV-SDF-1α-GFP was used to transfect myocardial fibroblasts which presented GFP green fluorescent expression and could secrete SDF-1α. The small animal ultrasound system showed that rat cardiac functions of the lentivirus group and cell group were improved to different degrees, myocardial ischemic necrosis zones of lentivirus group and cell group were reduced, and differences had statistical significances (P<0.05). Immunofluorescence showed that expressions of stem cellular markers c-kit, CD34, nkx2.5 and nanog in myocardial tissue ischemic zones in both the lentivirus group and cell group increased, and differences through inter-group comparison had statistical significances (P<0.05). CONCLUSION SDF-1α can promote migration and proliferation of stem cells into the myocardial ischemic necrosis zone, participate in repair of the myocardial necrosis zone, and improve cardiac function.
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Affiliation(s)
- Xinhua Cai
- Department of Histology and Embryology, Xinxiang Medical UniversityXinxiang 453003, Henan Province, China
| | - Zhanzhan Zhu
- The 7th People’s Hospital of ZhengzhouZhengzhou 450006, Henan Province, China
| | - Yongchun Zhang
- Department of Cardiology, The First Affiliated Hospital of Xinxiang Medical UniversityWeihui 453100, Henan Province, China
| | - Xiangqin Tian
- Department of Histology and Embryology, Xinxiang Medical UniversityXinxiang 453003, Henan Province, China
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Sebastian S, Hourd P, Chandra A, Williams DJ, Medcalf N. The management of risk and investment in cell therapy process development: a case study for neurodegenerative disease. Regen Med 2019; 14:465-488. [PMID: 31210581 DOI: 10.2217/rme-2018-0081] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Cell-based therapies must achieve clinical efficacy and safety with reproducible and cost-effective manufacturing. This study addresses process development issues using the exemplar of a human pluripotent stem cell-based dopaminergic neuron cell therapy product. Early identification and correction of risks to product safety and the manufacturing process reduces the expensive and time-consuming bridging studies later in development. A New Product Introduction map was used to determine the developmental requirements specific to the product. Systematic Risk Analysis is exemplified here. Expected current value-based prioritization guides decisions about the sequence of process studies and whether and if an early abandonment of further research is appropriate. The application of the three tools enabled prioritization of the development studies.
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Affiliation(s)
- Sujith Sebastian
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical & Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
| | - Paul Hourd
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical & Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
| | - Amit Chandra
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical & Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
| | - David J Williams
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical & Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
| | - Nicholas Medcalf
- Centre for Biological Engineering, Wolfson School of Mechanical, Electrical & Manufacturing Engineering, Loughborough University, Loughborough, Leicestershire, LE11 3TU, UK
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Qi S, Zhang P, Ma M, Yao M, Wu J, Mäkilä E, Salonen J, Ruskoaho H, Xu Y, Santos HA, Zhang H. Cellular Internalization-Induced Aggregation of Porous Silicon Nanoparticles for Ultrasound Imaging and Protein-Mediated Protection of Stem Cells. SMALL (WEINHEIM AN DER BERGSTRASSE, GERMANY) 2019; 15:e1804332. [PMID: 30488562 DOI: 10.1002/smll.201804332] [Citation(s) in RCA: 38] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Revised: 11/14/2018] [Indexed: 05/19/2023]
Abstract
Nanotechnology employs multifunctional engineered materials in the nanoscale range that provides many opportunities for translational stem cell research and therapy. Here, a cell-penetrating peptide (virus-1 transactivator of transcription)-conjugated, porous silicon nanoparticle (TPSi NP) loaded with the Wnt3a protein to increase both the cell survival rate and the delivery precision of stem cell transplantation via a combinational theranostic strategy is presented. The TPSi NP with a pore size of 10.7 nm and inorganic framework enables high-efficiency loading of Wnt3a, prolongs Wnt3a release, and increases antioxidative stress activity in the labeled mesenchymal stem cells (MSCs), which are highly beneficial properties for cell protection in stem cell therapy for myocardial infarction. It is confirmed that the intracellular aggregation of TPSi NPs can highly amplify the acoustic scattering of the labeled MSCs, resulting in a 2.3-fold increase in the ultrasound (US) signal compared with that of unlabeled MSCs. The translational potential of the designed nanoagent for real-time US imaging-guided stem cell transplantation is confirmed via intramyocardial injection of labeled MSCs in a nude mouse model. It is proposed that the intracellular aggregation of protein drug-loaded TPSi NPs could be a simple but robust strategy for improving the therapeutic effect of stem cell therapy.
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Affiliation(s)
- Shengcai Qi
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Pengfei Zhang
- The Key Laboratory of Cardiovascular Remodeling and Function Research of Chinese Ministry of Education, Department of Cardiology, Qilu Hospital of Shandong University, Jinan, Shandong, 250012, China
| | - Ming Ma
- State Key Laboratory of High Performance Ceramics and Superfine Microstructures, Shanghai Institute of Ceramics, Chinese Academy of Sciences, Shanghai, 200050, China
- Department of Pharmaceutical Science Laboratory, Åbo Akademi University, Turku, 20520, Finland
| | - Minghua Yao
- Department of Pharmaceutical Science Laboratory, Åbo Akademi University, Turku, 20520, Finland
| | - Jinjin Wu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Ermei Mäkilä
- Department of Physics and Astronomy, University of Turku, Turku, 20014, Finland
| | - Jarno Salonen
- Department of Physics and Astronomy, University of Turku, Turku, 20014, Finland
| | - Heikki Ruskoaho
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland
| | - Yuanzhi Xu
- Department of Stomatology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai, 200072, China
| | - Hélder A Santos
- Drug Research Program, Faculty of Pharmacy, University of Helsinki, FI-00014, Helsinki, Finland
| | - Hongbo Zhang
- Department of Pharmaceutical Science Laboratory, Åbo Akademi University, Turku, 20520, Finland
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49
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Huang K, Hu S, Cheng K. A New Era of Cardiac Cell Therapy: Opportunities and Challenges. Adv Healthc Mater 2019; 8:e1801011. [PMID: 30548836 PMCID: PMC6368830 DOI: 10.1002/adhm.201801011] [Citation(s) in RCA: 40] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Revised: 11/05/2018] [Indexed: 12/15/2022]
Abstract
Myocardial infarction (MI), caused by coronary heart disease (CHD), remains one of the most common causes of death in the United States. Over the last few decades, scientists have invested considerable resources on the study and development of cell therapies for myocardial regeneration after MI. However, due to a number of limitations, they are not yet readily available for clinical applications. Mounting evidence supports the theory that paracrine products are the main contributors to the regenerative effects attributed to these cell therapies. The next generation of cell-based MI therapies will identify and isolate cell products and derivatives, integrate them with biocompatible materials and technologies, and use them for the regeneration of damaged myocardial tissue. This review discusses the progress made thus far in pursuit of this new generation of cell therapies. Their fundamental regenerative mechanisms, their potential to combine with other therapeutic products, and their role in shaping new clinical approaches for heart tissue engineering, are addressed.
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Affiliation(s)
- Ke Huang
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27607, USA
| | - Shiqi Hu
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27607, USA
| | - Ke Cheng
- Department of Molecular Biomedical Sciences and Comparative Medicine Institute, North Carolina State University, Raleigh, NC, 27607, USA
- Joint Department of Biomedical Engineering, University of North Carolina at Chapel Hill and North Carolina State University, Raleigh, NC, 27607, USA
- Pharmacoengineeirng and Molecular Pharmaceutics Division, University of North Carolina at Chapel Hill, Chapel Hill, NC, 27599, USA
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McKown EN, DeAguero JL, Canan BD, Kilic A, Zhu Y, Janssen PM, Delfín DA. Impaired adhesion of induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) to isolated extracellular matrix from failing hearts. Heliyon 2018; 4:e00870. [PMID: 30364772 PMCID: PMC6197956 DOI: 10.1016/j.heliyon.2018.e00870] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Revised: 09/21/2018] [Accepted: 10/15/2018] [Indexed: 11/18/2022] Open
Abstract
We tested the hypothesis that induced pluripotent stem cell-derived cardiac progenitor cells (iPSC-CPCs) are less able to adhere to the extracellular matrix (ECM) derived from failing human hearts with dilated cardiomyopathy compared to nonfailing human heart ECM. We also hypothesized that morphological development, cell beating rates, and mRNA levels of Nkx2.5 and cardiac troponin T would be altered after culturing the iPSC-CPCs on the failing heart ECM under cardiomyocyte differentiation conditions. We used microscopy to distinguish between adhered and unadhered cells, and to determine morphological development and cell beating. We used qPCR to determine mRNA levels. iPSC-CPCs show a significantly reduced ability to adhere to the ECM of failing hearts and higher expression of Nkx2.5 mRNA. However, morphological development, cell beating rates, and cardiac troponin T levels were not significantly altered in the cells cultured on the failing heart ECM. Our study shows that the failing heart ECM from patients with dilated cardiomyopathy impairs initial iPSC-CPC adhesion and may have a modest effect on the ability of the cells to transdifferentiate into cardiomyocytes.
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Affiliation(s)
- Elizabeth N. McKown
- The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131, USA
| | - Joshua L. DeAguero
- The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131, USA
| | - Benjamin D. Canan
- The Ohio State University College of Medicine, Department of Physiology and Cell Biology and the Davis Heart Lung Research Institute, 200 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA
| | - Ahmet Kilic
- The Ohio State University College of Medicine, Department of Surgery and the Davis Heart Lung Research Institute, Richard M. Ross Heart Hospital, 452 West 10th Ave., Columbus, OH 43210, USA
| | - Yiliang Zhu
- The University of New Mexico School of Medicine, Department of Internal Medicine, MSC10 5550, 1 University of New Mexico, Albuquerque, NM 87131, USA
| | - Paul M.L. Janssen
- The Ohio State University College of Medicine, Department of Physiology and Cell Biology and the Davis Heart Lung Research Institute, 200 Hamilton Hall, 1645 Neil Avenue, Columbus, OH 43210, USA
| | - Dawn A. Delfín
- The University of New Mexico College of Pharmacy, Department of Pharmaceutical Sciences, MSC09 5360, 1 University of New Mexico, Albuquerque, NM 87131, USA
- Corresponding author.
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