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Hetta HF, Elsaghir A, Sijercic VC, Ahmed AK, Gad SA, Zeleke MS, Alanazi FE, Ramadan YN. Clinical Progress in Mesenchymal Stem Cell Therapy: A Focus on Rheumatic Diseases. Immun Inflamm Dis 2025; 13:e70189. [PMID: 40353645 PMCID: PMC12067559 DOI: 10.1002/iid3.70189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2023] [Revised: 05/10/2024] [Accepted: 03/21/2025] [Indexed: 05/14/2025] Open
Abstract
BACKGROUND Rheumatic diseases are chronic immune-mediated disorders affecting multiple organ systems and significantly impairing patients' quality of life. Current treatments primarily provide symptomatic relief without offering a cure. Mesenchymal stem cells (MSCs) have emerged as a promising therapeutic option due to their ability to differentiate into various cell types and their immunomodulatory, anti-inflammatory, and regenerative properties. This review aims to summarize the clinical progress of MSC therapy in rheumatic diseases, highlight key findings from preclinical and clinical studies, and discuss challenges and future directions. METHODOLOGY A comprehensive review of preclinical and clinical studies on MSC therapy in rheumatic diseases, including systemic lupus erythematosus, rheumatoid arthritis, ankylosing spondylitis, osteoarthritis, osteoporosis, Sjögren's syndrome, Crohn's disease, fibromyalgia, systemic sclerosis, dermatomyositis, and polymyositis, was conducted. Emerging strategies to enhance MSC efficacy and overcome current limitations were also analyzed. RESULTS AND DISCUSSION Evidence from preclinical and clinical studies suggests that MSC therapy can reduce inflammation, modulate immune responses, and promote tissue repair in various rheumatic diseases. Clinical trials have demonstrated potential benefits, including symptom relief and disease progression delay. However, challenges such as variability in treatment response, optimal cell source and dosing, long-term safety concerns, and regulatory hurdles remain significant barriers to clinical translation. Standardized protocols and further research are required to optimize MSC application. CONCLUSION MSC therapy holds promise for managing rheumatic diseases, offering potential disease-modifying effects beyond conventional treatments. However, large-scale, well-controlled clinical trials are essential to establish efficacy, safety, and long-term therapeutic potential. Addressing current limitations through optimized treatment protocols and regulatory frameworks will be key to its successful integration into clinical practice.
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Affiliation(s)
- Helal F. Hetta
- Division of Microbiology, Immunology and Biotechnology, Department of Natural Products and Alternative Medicine, Faculty of PharmacyUniversity of TabukTabukSaudi Arabia
| | - Alaa Elsaghir
- Department of Microbiology and Immunology, Faculty of PharmacyAssiut UniversityAssiutEgypt
| | | | - Abdulrahman K. Ahmed
- Emergency Medicine Unit, Department of Anaethesia and Intensive Care, Faculty of MedicineAssiut UniversityAssiutEgypt
| | - Sayed A. Gad
- Emergency Medicine Unit, Department of Anaethesia and Intensive Care, Faculty of MedicineAssiut UniversityAssiutEgypt
| | - Mahlet S. Zeleke
- Menelik II Medical and Health Science CollegeAddis AbabaEthiopia
| | - Fawaz E. Alanazi
- Department of Pharmacology and Toxicology, Faculty of PharmacyUniversity of TabukTabukSaudi Arabia
| | - Yasmin N. Ramadan
- Department of Microbiology and Immunology, Faculty of PharmacyAssiut UniversityAssiutEgypt
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Guo X, Zhang M, Xu Z, Yu Y, Shen Z. CRISPR/Cas9-mediated generation of AP-1 activity reporter cell line in human embryonic stem cell (WAe007-A-5). Stem Cell Res 2024; 81:103557. [PMID: 39276528 DOI: 10.1016/j.scr.2024.103557] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2024] [Revised: 08/14/2024] [Accepted: 09/09/2024] [Indexed: 09/17/2024] Open
Abstract
Activator protein 1 (AP-1) is involved in cell fate determination and function. To monitor the AP-1 activity, we cloned a AP-1 binding sites fragment into the upstream of minimal TATA-box promoter, then a luciferase-GFP reporter (LuciGFP) was designated to the downstream of the promoter. With CRISPR/Cas9, the AP-1-LuciGFP reporter was introduced into AAVS1 locus, a safe harbor for gene editing. Thus, this AP-1-LuciGFP reporter cell line could be subjected to monitor the AP-1 activity during the cell differentiation, cell fate transition and disease modeling.
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Affiliation(s)
- Xingyou Guo
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, PR China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, PR China; Department of Vascular Surgery, Suqian First Hospital, Suqian 223800, Jiangsu, PR China
| | - Meng Zhang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, PR China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, PR China
| | - Zhanglei Xu
- Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, PR China; School of Biology & Basic Medical Sciences, Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, PR China
| | - You Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, PR China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, PR China.
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, PR China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, PR China.
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Hu Y, Zou Y, Qiao L, Lin L. Integrative proteomic and metabolomic elucidation of cardiomyopathy with in vivo and in vitro models and clinical samples. Mol Ther 2024; 32:3288-3312. [PMID: 39233439 PMCID: PMC11489546 DOI: 10.1016/j.ymthe.2024.08.030] [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: 04/30/2024] [Revised: 07/16/2024] [Accepted: 08/30/2024] [Indexed: 09/06/2024] Open
Abstract
Cardiomyopathy is a prevalent cardiovascular disease that affects individuals of all ages and can lead to life-threatening heart failure. Despite its variety in types, each with distinct characteristics and causes, our understanding of cardiomyopathy at a systematic biology level remains incomplete. Mass spectrometry-based techniques have emerged as powerful tools, providing a comprehensive view of the molecular landscape and aiding in the discovery of biomarkers and elucidation of mechanisms. This review highlights the significant potential of integrating proteomic and metabolomic approaches with specialized databases to identify biomarkers and therapeutic targets across different types of cardiomyopathies. In vivo and in vitro models, such as genetically modified mice, patient-derived or induced pluripotent stem cells, and organ chips, are invaluable in exploring the pathophysiological complexities of this disease. By integrating omics approaches with these sophisticated modeling systems, our comprehension of the molecular underpinnings of cardiomyopathy can be greatly enhanced, facilitating the development of diagnostic markers and therapeutic strategies. Among the promising therapeutic targets are those involved in extracellular matrix remodeling, sarcomere damage, and metabolic remodeling. These targets hold the potential to advance precision therapy in cardiomyopathy, offering hope for more effective treatments tailored to the specific molecular profiles of patients.
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Affiliation(s)
- Yiwei Hu
- Department of Chemistry, Zhongshan Hospital, and Minhang Hospital, Fudan University, Shanghai 200000, China
| | - Yunzeng Zou
- Department of Chemistry, Zhongshan Hospital, and Minhang Hospital, Fudan University, Shanghai 200000, China.
| | - Liang Qiao
- Department of Chemistry, Zhongshan Hospital, and Minhang Hospital, Fudan University, Shanghai 200000, China.
| | - Ling Lin
- Department of Chemistry, Zhongshan Hospital, and Minhang Hospital, Fudan University, Shanghai 200000, China.
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Fan C, Qin K, Iroegbu CD, Xiang K, Gong Y, Guan Q, Wang W, Peng J, Guo J, Wu X, Yang J. Magnesium lithospermate B enhances the potential of human-induced pluripotent stem cell-derived cardiomyocytes for myocardial repair. Chin Med J (Engl) 2024; 137:1857-1869. [PMID: 38221772 PMCID: PMC12077548 DOI: 10.1097/cm9.0000000000002867] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2023] [Indexed: 01/16/2024] Open
Abstract
BACKGROUND We previously reported that activation of the cell cycle in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) enhances their remuscularization capacity after human cardiac muscle patch transplantation in infarcted mouse hearts. Herein, we sought to identify the effect of magnesium lithospermate B (MLB) on hiPSC-CMs during myocardial repair using a myocardial infarction (MI) mouse model. METHODS In C57BL/6 mice, MI was surgically induced by ligating the left anterior descending coronary artery. The mice were randomly divided into five groups ( n = 10 per group); a MI group (treated with phosphate-buffered saline only), a hiPSC-CMs group, a MLB group, a hiPSC-CMs + MLB group, and a Sham operation group. Cardiac function and MLB therapeutic efficacy were evaluated by echocardiography and histochemical staining 4 weeks after surgery. To identify the associated mechanism, nuclear factor (NF)-κB p65 and intercellular cell adhesion molecule-1 (ICAM1) signals, cell adhesion ability, generation of reactive oxygen species, and rates of apoptosis were detected in human umbilical vein endothelial cells (HUVECs) and hiPSC-CMs. RESULTS After 4 weeks of transplantation, the number of cells that engrafted in the hiPSC-CMs + MLB group was about five times higher than those in the hiPSC-CMs group. Additionally, MLB treatment significantly reduced tohoku hospital pediatrics-1 (THP-1) cell adhesion, ICAM1 expression, NF-κB nuclear translocation, reactive oxygen species production, NF-κB p65 phosphorylation, and cell apoptosis in HUVECs cultured under hypoxia. Similarly, treatment with MLB significantly inhibited the apoptosis of hiPSC-CMs via enhancing signal transducer and activator of transcription 3 (STAT3) phosphorylation and B-cell lymphoma-2 (BCL2) expression, promoting STAT3 nuclear translocation, and downregulating BCL2-Associated X, dual specificity phosphatase 2 (DUSP2), and cleaved-caspase-3 expression under hypoxia. Furthermore, MLB significantly suppressed the production of malondialdehyde and lactate dehydrogenase and the reduction in glutathione content induced by hypoxia in both HUVECs and hiPSC-CMs in vitro . CONCLUSIONS MLB significantly enhanced the potential of hiPSC-CMs in repairing injured myocardium by improving endothelial cell function via the NF-κB/ICAM1 pathway and inhibiting hiPSC-CMs apoptosis via the DUSP2/STAT3 pathway.
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Affiliation(s)
- Chengming Fan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China
- Hunan Fangsheng Pharmaceutical Co., Ltd., Changsha, Hunan 410000, China
| | - Kele Qin
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Chukwuemeka Daniel Iroegbu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Kun Xiang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Yibo Gong
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Qing Guan
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
| | - Wenxiang Wang
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 41000, China
| | - Jun Peng
- Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China
| | - Jianjun Guo
- Hunan Fangsheng Pharmaceutical Co., Ltd., Changsha, Hunan 410000, China
| | - Xun Wu
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
- Department of Thoracic Surgery, The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan 41000, China
| | - Jinfu Yang
- Department of Cardiovascular Surgery, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China
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Loukelis K, Koutsomarkos N, Mikos AG, Chatzinikolaidou M. Advances in 3D bioprinting for regenerative medicine applications. Regen Biomater 2024; 11:rbae033. [PMID: 38845855 PMCID: PMC11153344 DOI: 10.1093/rb/rbae033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2023] [Revised: 03/13/2024] [Accepted: 03/17/2024] [Indexed: 06/09/2024] Open
Abstract
Biofabrication techniques allow for the construction of biocompatible and biofunctional structures composed from biomaterials, cells and biomolecules. Bioprinting is an emerging 3D printing method which utilizes biomaterial-based mixtures with cells and other biological constituents into printable suspensions known as bioinks. Coupled with automated design protocols and based on different modes for droplet deposition, 3D bioprinters are able to fabricate hydrogel-based objects with specific architecture and geometrical properties, providing the necessary environment that promotes cell growth and directs cell differentiation towards application-related lineages. For the preparation of such bioinks, various water-soluble biomaterials have been employed, including natural and synthetic biopolymers, and inorganic materials. Bioprinted constructs are considered to be one of the most promising avenues in regenerative medicine due to their native organ biomimicry. For a successful application, the bioprinted constructs should meet particular criteria such as optimal biological response, mechanical properties similar to the target tissue, high levels of reproducibility and printing fidelity, but also increased upscaling capability. In this review, we highlight the most recent advances in bioprinting, focusing on the regeneration of various tissues including bone, cartilage, cardiovascular, neural, skin and other organs such as liver, kidney, pancreas and lungs. We discuss the rapidly developing co-culture bioprinting systems used to resemble the complexity of tissues and organs and the crosstalk between various cell populations towards regeneration. Moreover, we report on the basic physical principles governing 3D bioprinting, and the ideal bioink properties based on the biomaterials' regenerative potential. We examine and critically discuss the present status of 3D bioprinting regarding its applicability and current limitations that need to be overcome to establish it at the forefront of artificial organ production and transplantation.
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Affiliation(s)
- Konstantinos Loukelis
- Department of Materials Science and Technology, University of Crete, Heraklion 70013, Greece
| | - Nikos Koutsomarkos
- Department of Materials Science and Technology, University of Crete, Heraklion 70013, Greece
| | - Antonios G Mikos
- Department of Bioengineering, Rice University, Houston, TX 77030, USA
| | - Maria Chatzinikolaidou
- Department of Materials Science and Technology, University of Crete, Heraklion 70013, Greece
- Institute of Electronic Structure and Laser (IESL), Foundation for Research and Technology Hellas (FORTH), Heraklion 70013, Greece
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Guo H, Hang C, Lin B, Lin Z, Xiong H, Zhang M, Lu R, Liu J, Shi D, Xie D, Liu Y, Liang D, Yang J, Chen YH. HAND factors regulate cardiac lineage commitment and differentiation from human pluripotent stem cells. Stem Cell Res Ther 2024; 15:31. [PMID: 38317221 PMCID: PMC10845658 DOI: 10.1186/s13287-024-03649-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Accepted: 01/25/2024] [Indexed: 02/07/2024] Open
Abstract
BACKGROUND Transcription factors HAND1 and HAND2 (HAND1/2) play significant roles in cardiac organogenesis. Abnormal expression and deficiency of HAND1/2 result in severe cardiac defects. However, the function and mechanism of HAND1/2 in regulating human early cardiac lineage commitment and differentiation are still unclear. METHODS With NKX2.5eGFP H9 human embryonic stem cells (hESCs), we established single and double knockout cell lines for HAND1 and HAND2, respectively, whose cardiomyocyte differentiation efficiency could be monitored by assessing NKX2.5-eGFP+ cells with flow cytometry. The expression of specific markers for heart fields and cardiomyocyte subtypes was examined by quantitative PCR, western blot and immunofluorescence staining. Microelectrode array and whole-cell patch clamp were performed to determine the electrophysiological characteristics of differentiated cardiomyocytes. The transcriptomic changes of HAND knockout cells were revealed by RNA sequencing. The HAND1/2 target genes were identified and validated experimentally by integrating with HAND1/2 chromatin immunoprecipitation sequencing data. RESULTS Either HAND1 or HAND2 knockout did not affect the cardiomyocyte differentiation kinetics, whereas depletion of HAND1/2 resulted in delayed differentiation onset. HAND1 knockout biased cardiac mesoderm toward second heart field progenitors at the expense of first heart field progenitors, leading to increased expression of atrial and outflow tract cardiomyocyte markers, which was further confirmed by the appearance of atrial-like action potentials. By contrast, HAND2 knockout cardiomyocytes had reduced expression of atrial cardiomyocyte markers and displayed ventricular-like action potentials. HAND1/2-deficient hESCs were more inclined to second heart field lineage and its derived cardiomyocytes with atrial-like action potentials than HAND1 single knockout during differentiation. Further mechanistic investigations suggested TBX5 as one of the downstream targets of HAND1/2, whose overexpression partially restored the abnormal cardiomyocyte differentiation in HAND1/2-deficient hESCs. CONCLUSIONS HAND1/2 have specific and redundant roles in cardiac lineage commitment and differentiation. These findings not only reveal the essential function of HAND1/2 in cardiac organogenesis, but also provide important information on the pathogenesis of HAND1/2 deficiency-related congenital heart diseases, which could potentially lead to new therapeutic strategies.
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Affiliation(s)
- Huixin Guo
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China
| | - Chengwen Hang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Bowen Lin
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Zheyi Lin
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Hui Xiong
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Mingshuai Zhang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Renhong Lu
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Junyang Liu
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Dan Shi
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
| | - Duanyang Xie
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Yi Liu
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
| | - Dandan Liang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China
- Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai, 200092, China
| | - Jian Yang
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China.
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China.
- Department of Cell Biology, Tongji University School of Medicine, Shanghai, 200092, China.
- Research Units of Origin and Regulation of Heart Rhythm, Chinese Academy of Medical Sciences, Shanghai, 200092, China.
| | - Yi-Han Chen
- Department of Cardiology, The Second Hospital of Shanxi Medical University, Taiyuan, 030001, China.
- State Key Laboratory of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Arrhythmia Research Center, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Department of Cardiology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, 200120, China.
- Shanghai Frontiers Center of Nanocatalytic Medicine, Shanghai, 200092, China.
- Department of Pathology and Pathophysiology, Tongji University School of Medicine, Shanghai, 200092, China.
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Saito Y, Nose N, Iida T, Akazawa K, Kanno T, Fujimoto Y, Sasaki T, Akehi M, Higuchi T, Akagi S, Yoshida M, Miyoshi T, Ito H, Nakamura K. In vivo tracking transplanted cardiomyocytes derived from human induced pluripotent stem cells using nuclear medicine imaging. Front Cardiovasc Med 2023; 10:1261330. [PMID: 37745108 PMCID: PMC10512708 DOI: 10.3389/fcvm.2023.1261330] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 08/28/2023] [Indexed: 09/26/2023] Open
Abstract
Introduction Transplantation of human induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is a promising treatment for heart failure. Information on long-term cell engraftment after transplantation is clinically important. However, clinically applicable evaluation methods have not yet been established. Methods In this study, to noninvasively assess transplanted cell engraftment, human SLC5A5, which encodes a sodium/iodide symporter (NIS) that transports radioactive tracers such as 125I, 18F-tetrafluoroborate (TFB), and 99mTc-pertechnetate (99mTcO4-), was transduced into human induced pluripotent stem cells (iPSCs), and nuclear medicine imaging was used to track engrafted human iPSC-CMs. Results To evaluate the pluripotency of NIS-expressing human iPSCs, they were subcutaneously transplanted into immunodeficient rats. Teratomas were detected by 99mTcO4- single photon emission computed tomography (SPECT/CT) imaging. NIS expression and the uptake ability of 125I were maintained in purified human iPSC-CMs. NIS-expressing human iPSC-CMs transplanted into immunodeficient rats could be detected over time using 99mTcO4- SPECT/CT imaging. Unexpectedly, NIS expression affected cell proliferation of human iPSCs and iPSC-derived cells. Discussion Such functionally designed iPSC-CMs have potential clinical applications as a noninvasive method of grafted cell evaluation, but further studies are needed to determine the effects of NIS transduction on cellular characteristics and functions.
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Affiliation(s)
- Yukihiro Saito
- Department of Cardiovascular Medicine, Okayama University Hospital, Okayama, Japan
| | - Naoko Nose
- Molecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toshihiro Iida
- Department of Cardiovascular Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Kaoru Akazawa
- Department of Cardiovascular Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takayuki Kanno
- Molecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Yuki Fujimoto
- Molecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takanori Sasaki
- Okayama Medical Innovation Center, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masaru Akehi
- Okayama Medical Innovation Center, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Takahiro Higuchi
- Molecular Imaging Project of RECTOR Program, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
- Department of Nuclear Medicine, University Hospital Würzburg, Würzburg, Germany
- Comprehensive Heart Failure Center, University Hospital Würzburg, Würzburg, Germany
| | - Satoshi Akagi
- Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Masashi Yoshida
- Department of Chronic Kidney Disease and Cardiovascular Disease, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Toru Miyoshi
- Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
| | - Hiroshi Ito
- Department of General Internal Medicine 3, Kawasaki Medical School, Okayama, Japan
| | - Kazufumi Nakamura
- Department of Cardiovascular Medicine, Faculty of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama, Japan
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Hao KL, Zhai QC, Gu Y, Chen YQ, Wang YN, Liu R, Yan SP, Wang Y, Shi YF, Lei W, Shen ZY, Xu Y, Hu SJ. Disturbance of suprachiasmatic nucleus function improves cardiac repair after myocardial infarction by IGF2-mediated macrophage transition. Acta Pharmacol Sin 2023; 44:1612-1624. [PMID: 36747104 PMCID: PMC10374569 DOI: 10.1038/s41401-023-01059-w] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/26/2022] [Accepted: 01/17/2023] [Indexed: 02/08/2023]
Abstract
Suprachiasmatic nucleus (SCN) in mammals functions as the master circadian pacemaker that coordinates temporal organization of physiological processes with the environmental light/dark cycles. But the causative links between SCN and cardiovascular diseases, specifically the reparative responses after myocardial infarction (MI), remain largely unknown. In this study we disrupted mouse SCN function to investigate the role of SCN in cardiac dysfunction post-MI. Bilateral ablation of the SCN (SCNx) was generated in mice by electrical lesion; myocardial infarction was induced via ligation of the mid-left anterior descending artery (LAD); cardiac function was assessed using echocardiography. We showed that SCN ablation significantly alleviated MI-induced cardiac dysfunction and cardiac fibrosis, and promoted angiogenesis. RNA sequencing revealed differentially expressed genes in the heart of SCNx mice from D0 to D3 post-MI, which were functionally associated with the inflammatory response and cytokine-cytokine receptor interaction. Notably, the expression levels of insulin-like growth factor 2 (Igf2) in the heart and serum IGF2 concentration were significantly elevated in SCNx mice on D3 post-MI. Stimulation of murine peritoneal macrophages in vitro with serum isolated from SCNx mice on D3 post-MI accelerated the transition of anti-inflammatory macrophages, while antibody-mediated neutralization of IGF2 receptor blocked the macrophage transition toward the anti-inflammatory phenotype in vitro as well as the corresponding cardioprotective effects observed in SCNx mice post-MI. In addition, disruption of mouse SCN function by exposure to a desynchronizing condition (constant light) caused similar protective effects accompanied by elevated IGF2 expression on D3 post-MI. Finally, mice deficient in the circadian core clock genes (Ckm-cre; Bmal1f/f mice or Per1/2 double knockout) did not lead to increased serum IGF2 concentration and showed no protective roles in post-MI, suggesting that the cardioprotective effect observed in this study was mediated particularly by the SCN itself, but not by self-sustained molecular clock. Together, we demonstrate that inhibition of SCN function promotes Igf2 expression, which leads to macrophage transition and improves cardiac repair post-MI.
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Affiliation(s)
- Kai-Li Hao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Qiao-Cheng Zhai
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Yue Gu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Yue-Qiu Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Ya-Ning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Rui Liu
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Shi-Ping Yan
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China
| | - Ying Wang
- CAS Key Laboratory of Tissue Microenvironment and Tumor, Shanghai Institute of Nutrition and Health, Chinese Academy of Sciences, Shanghai, 200031, China
| | - Yu-Fang Shi
- The First Affiliated Hospital of Soochow University, State Key Laboratory of Radiation Medicine and Protection, Institutes for Translational Medicine, Suzhou Medical College, Soochow University, Suzhou, 215123, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| | - Zhen-Ya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
| | - Ying Xu
- Jiangsu Key Laboratory of Neuropsychiatric Diseases and Cambridge-Su Genomic Resource Center, Suzhou Medical College, Soochow University, Suzhou, 215123, China.
| | - Shi-Jun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, 215000, China.
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9
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Li Q, Shao L, Li L, Shen H, Yu Y, Shen Z. Generation of a human embryonic stem cell line targeted homozygous deletion of BMP10 (WAe007-A-2) by CRISPR/Cas9-dgRNA. Stem Cell Res 2022; 65:102942. [PMID: 36257094 DOI: 10.1016/j.scr.2022.102942] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2022] [Accepted: 10/12/2022] [Indexed: 11/05/2022] Open
Abstract
BMP10 signaling has been implicated in regulation of cardiovascular cell fate determination and diseases, while the underlying molecular mechanism still remains uncertain. Here, the human embryonic stem cell line (H7-BMP10del) with homozygous deletion of BMP10 was generated by CRISPR/Cas9 method. Thus, the crosstalk related to BMP10 signaling could be investigated in cell fate determination and the molecular pathogenesis of cardiovascular disease.
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Affiliation(s)
- Qian Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Lianbo Shao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Luo Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Han Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - You Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
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10
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Xiao Y, Chen Y, Shao C, Wang Y, Hu S, Lei W. Strategies to improve the therapeutic effect of pluripotent stem cell-derived cardiomyocytes on myocardial infarction. Front Bioeng Biotechnol 2022; 10:973496. [PMID: 35992358 PMCID: PMC9388750 DOI: 10.3389/fbioe.2022.973496] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2022] [Accepted: 07/11/2022] [Indexed: 11/20/2022] Open
Abstract
Myocardial infarction (MI) is a common cardiovascular disease caused by permanent loss of cardiomyocytes and the formation of scar tissue due to myocardial ischemia. Mammalian cardiomyocytes lose their ability to proliferate almost completely in adulthood and are unable to repair the damage caused by MI. Therefore, transplantation of exogenous cells into the injured area for treatment becomes a promising strategy. Pluripotent stem cells (PSCs) have the ability to proliferate and differentiate into various cellular populations indefinitely, and pluripotent stem cell-derived cardiomyocytes (PSC-CMs) transplanted into areas of injury can compensate for part of the injuries and are considered to be one of the most promising sources for cell replacement therapy. However, the low transplantation rate and survival rate of currently transplanted PSC-CMs limit their ability to treat MI. This article focuses on the strategies of current research for improving the therapeutic efficacy of PSC-CMs, aiming to provide some inspiration and ideas for subsequent researchers to further enhance the transplantation rate and survival rate of PSC-CMs and ultimately improve cardiac function.
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Affiliation(s)
- Yang Xiao
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Chunlai Shao
- Department of Cardiology, The Second Affiliated Hospital of Soochow University, Suzhou, China
| | - Yaning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
- *Correspondence: Wei Lei, ; Shijun Hu,
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital and Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College, Soochow University, Suzhou, China
- *Correspondence: Wei Lei, ; Shijun Hu,
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11
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Margiana R, Markov A, Zekiy AO, Hamza MU, Al-Dabbagh KA, Al-Zubaidi SH, Hameed NM, Ahmad I, Sivaraman R, Kzar HH, Al-Gazally ME, Mustafa YF, Siahmansouri H. Clinical application of mesenchymal stem cell in regenerative medicine: a narrative review. Stem Cell Res Ther 2022; 13:366. [PMID: 35902958 PMCID: PMC9330677 DOI: 10.1186/s13287-022-03054-0] [Citation(s) in RCA: 189] [Impact Index Per Article: 63.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2022] [Accepted: 07/18/2022] [Indexed: 12/16/2022] Open
Abstract
The multipotency property of mesenchymal stem cells (MSCs) has attained worldwide consideration because of their immense potential for immunomodulation and their therapeutic function in tissue regeneration. MSCs can migrate to tissue injury areas to contribute to immune modulation, secrete anti-inflammatory cytokines and hide themselves from the immune system. Certainly, various investigations have revealed anti-inflammatory, anti-aging, reconstruction, and wound healing potentials of MSCs in many in vitro and in vivo models. Moreover, current progresses in the field of MSCs biology have facilitated the progress of particular guidelines and quality control approaches, which eventually lead to clinical application of MSCs. In this literature, we provided a brief overview of immunoregulatory characteristics and immunosuppressive activities of MSCs. In addition, we discussed the enhancement, utilization, and therapeutic responses of MSCs in neural, liver, kidney, bone, heart diseases, and wound healing.
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Affiliation(s)
- Ria Margiana
- Department of Anatomy, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Master's Programme Biomedical Sciences, Faculty of Medicine, Universitas Indonesia, Jakarta, Indonesia.,Dr. Soetomo General Academic Hospital, Surabaya, Indonesia
| | - Alexander Markov
- Tyumen State Medical University, Tyumen, Russian Federation.,Tyumen Industrial University, Tyumen, Russian Federation
| | - Angelina O Zekiy
- Department of Prosthetic Dentistry, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia
| | | | | | | | - Noora M Hameed
- Anesthesia Techniques, Al-Nisour University College, Baghdad, Iraq
| | - Irshad Ahmad
- Department of Medical Rehabilitation Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - R Sivaraman
- Department of Mathematics, Dwaraka Doss Goverdhan Doss Vaishnav College, Arumbakkam, University of Madras, Chennai, India
| | - Hamzah H Kzar
- Veterinary Medicine College, Al-Qasim Green University, Al-Qasim, Iraq
| | | | - Yasser Fakri Mustafa
- Department of Pharmaceutical Chemistry, College of Pharmacy, University of Mosul, Mosul, 41001, Iraq
| | - Homayoon Siahmansouri
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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12
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In vitro maturation of human pluripotent stem cell-derived cardiomyocyte: A promising approach for cell therapy. JOURNAL OF ANIMAL REPRODUCTION AND BIOTECHNOLOGY 2022. [DOI: 10.12750/jarb.37.2.67] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022] Open
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13
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Yu Y, Shen H, Zhu J, Cao X, Li Q, Shao L, Shen Z. Generation of Marfan patient specific iPSCs (ICSSUi001-A) carrying a novel heterozygous mutation in FBN1 gene. Stem Cell Res 2022; 60:102720. [DOI: 10.1016/j.scr.2022.102720] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Accepted: 02/21/2022] [Indexed: 11/29/2022] Open
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14
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Zhu J, Chen Y, Cao X, Li Q, Shao L, Teng X, Yu Y, Shen Z. Generation of a Human iPSC (ICSSUi002-A) with MTHFR SNP (rs1801133, TT) from Thoracic Aortic Dissection Patient. Stem Cell Res 2022; 61:102753. [PMID: 35305471 DOI: 10.1016/j.scr.2022.102753] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/09/2022] [Revised: 03/06/2022] [Accepted: 03/11/2022] [Indexed: 11/20/2022] Open
Abstract
Thoracic aortic dissection is a devastating cardiovascular disease with an increasing annual incidence. The homozygous mutation in rs1801133 site has been accepted for decreased enzyme activity of mutant MTHFR protein, contributing to an accumulated homocysteine in blood. Recently, elevated homocysteine level is causally associated with an increased risk of cardiovascular disease. Conversely, the relationship between rs1801133 and thoracic aortic dissection is poorly understood. Here, the generated human induced pluripotent stem cell (iPSC) line provided a novel strategy for investigating the underlying mechanism of MTHFR mutation (rs1801133, TT) and its implication in the pathogenesis of thoracic aortic dissection.
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Affiliation(s)
- Jingze Zhu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Yihuan Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Xiangyu Cao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Qian Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China
| | - Lianbo Shao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China
| | - Xiaomei Teng
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China
| | - You Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Soochow University, Suzhou 215123, Jiangsu, China; Suzhou Medical College, Soochow University, Suzhou 215123, Jiangsu, China.
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15
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Li L, Zhou J, Han L, Wu X, Shi Y, Cui W, Zhang S, Hu Q, Wang J, Bai H, Liu H, Guo W, Feng D, Qu Y. The Specific Role of Reactive Astrocytes in Stroke. Front Cell Neurosci 2022; 16:850866. [PMID: 35321205 PMCID: PMC8934938 DOI: 10.3389/fncel.2022.850866] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2022] [Accepted: 02/15/2022] [Indexed: 01/05/2023] Open
Abstract
Astrocytes are essential in maintaining normal brain functions such as blood brain barrier (BBB) homeostasis and synapse formation as the most abundant cell type in the central nervous system (CNS). After the stroke, astrocytes are known as reactive astrocytes (RAs) because they are stimulated by various damage-associated molecular patterns (DAMPs) and cytokines, resulting in significant changes in their reactivity, gene expression, and functional characteristics. RAs perform multiple functions after stroke. The inflammatory response of RAs may aggravate neuro-inflammation and release toxic factors to exert neurological damage. However, RAs also reduce excitotoxicity and release neurotrophies to promote neuroprotection. Furthermore, RAs contribute to angiogenesis and axonal remodeling to promote neurological recovery. Therefore, RAs' biphasic roles and mechanisms make them an effective target for functional recovery after the stroke. In this review, we summarized the dynamic functional changes and internal molecular mechanisms of RAs, as well as their therapeutic potential and strategies, in order to comprehensively understand the role of RAs in the outcome of stroke disease and provide a new direction for the clinical treatment of stroke.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | - Yan Qu
- Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, China
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16
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Ye L, Yu Y, Zhao ZA, Zhao D, Ni X, Wang Y, Fang X, Yu M, Wang Y, Tang JM, Chen Y, Shen Z, Lei W, Hu S. Patient-specific iPSC-derived cardiomyocytes reveal abnormal regulation of FGF16 in a familial atrial septal defect. Cardiovasc Res 2022; 118:859-871. [PMID: 33956078 DOI: 10.1093/cvr/cvab154] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Accepted: 05/04/2021] [Indexed: 12/15/2022] Open
Abstract
AIMS Congenital heart disease (CHD) frequently occurs in newborns due to abnormal formation of the heart or major blood vessels. Mutations in the GATA4 gene, which encodes GATA binding protein 4, are responsible for atrial septal defect (ASD), a common CHD. This study aims to gain insights into the molecular mechanisms of CHD using human-induced pluripotent stem cells (iPSCs) from a family cohort with ASD. METHODS AND RESULTS Patient-specific iPSCs possess the same genetic information as the donor and can differentiate into various cell types from all three germ layers in vitro, thus presenting a promising approach for disease modelling and molecular mechanism research. Here, we generated a patient-specific iPSC line (iPSC-G4T280M) from a family cohort carrying a hereditary ASD mutation in GATA4 gene (T280M), as well as a human embryonic stem cell line (ESC-G4T280M) carrying the isogenic T280M mutation using the CRISPR/Cas9 genome editing method. The GATA4-mutant iPSCs and ESCs were then differentiated into cardiomyocytes (CMs) to model GATA4 mutation-associated ASD. We observed an obvious defect in cell proliferation in cardiomyocytes derived from both GATA4T280M-mutant iPSCs (iPSC-G4T280M-CMs) and ESCs (ESC-G4T280M-CMs), while the impaired proliferation ability of iPSC-G4T280M-CMs could be restored by gene correction. Integrated analysis of RNA-Seq and ChIP-Seq data indicated that FGF16 is a direct target of wild-type GATA4. However, the T280M mutation obstructed GATA4 occupancy at the FGF16 promoter region, leading to impaired activation of FGF16 transcription. Overexpression of FGF16 in GATA4-mutant cardiomyocytes rescued the cell proliferation defect. The direct relationship between GATA4T280M and ASD was demonstrated in a human iPSC model for the first time. CONCLUSIONS In summary, our study revealed the molecular mechanism of the GATA4T280M mutation in ASD. Understanding the roles of the GATA4-FGF16 axis in iPSC-CMs will shed light on heart development and provide novel insights for the treatment of ASD and other CHD disorders.
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Affiliation(s)
- Lingqun Ye
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - You Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Zhen-Ao Zhao
- Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou 075000, China
- Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou 075000, China
| | - Dandan Zhao
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Xuan Ni
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Yong Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Xing Fang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Yongming Wang
- State Key Laboratory of Genetic Engineering, School of Life Sciences, Zhongshan Hospital, Fudan University, Shanghai 200432, China
| | - Jun-Ming Tang
- Hubei Key Laboratory of Embryonic Stem Cell Research, School of Basic Medicine Science, Hubei University of Medicine, Shiyan 442000, China
| | - Ying Chen
- Central Lab, the Affiliated Wuxi Maternity and Child Health Care Hospital of Nanjing Medical University, Wuxi 214002, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou 215000, China
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17
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Ni X, Yang ZZ, Ye LQ, Han XL, Zhao DD, Ding FY, Ding N, Wu HC, Yu M, Xu GY, Zhao ZA, Lei W, Hu SJ. Establishment of an in vitro safety assessment model for lipid-lowering drugs using same-origin human pluripotent stem cell-derived cardiomyocytes and endothelial cells. Acta Pharmacol Sin 2022; 43:240-250. [PMID: 33686244 PMCID: PMC8724272 DOI: 10.1038/s41401-021-00621-8] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2020] [Accepted: 02/01/2021] [Indexed: 01/31/2023]
Abstract
Cardiovascular safety assessment is vital for drug development, yet human cardiovascular cell models are lacking. In vitro mass-generated human pluripotent stem cell (hPSC)-derived cardiovascular cells are a suitable cell model for preclinical cardiovascular safety evaluations. In this study, we established a preclinical toxicology model using same-origin hPSC-differentiated cardiomyocytes (hPSC-CMs) and endothelial cells (hPSC-ECs). For validation of this cell model, alirocumab, a human antibody against proprotein convertase subtilisin kexin type 9 (PCSK9), was selected as an emerging safe lipid-lowering drug; atorvastatin, a common statin (the most effective type of lipid-lowering drug), was used as a drug with reported side effects at high concentrations, while doxorubicin was chosen as a positive cardiotoxic drug. The cytotoxicity of these drugs was assessed using CCK8, ATP, and lactate dehydrogenase release assays at 24, 48, and 72 h. The influences of these drugs on cardiomyocyte electrophysiology were detected using the patch-clamp technique, while their effects on endothelial function were determined by tube formation and Dil-acetylated low-density lipoprotein (Dil-Ac-LDL) uptake assays. We showed that alirocumab did not affect the cell viability or cardiomyocyte electrophysiology in agreement with the clinical results. Atorvastatin (5-50 μM) dose-dependently decreased cardiovascular cell viability over time, and at a high concentration (50 μM, ~100 times the normal peak serum concentration in clinic), it affected the action potentials of hPSC-CMs and damaged tube formation and Dil-Ac-LDL uptake of hPSC-ECs. The results demonstrate that the established same-origin hPSC-derived cardiovascular cell model can be used to evaluate lipid-lowering drug safety in cardiovascular cells and allow highly accurate preclinical assessment of potential drugs.
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Affiliation(s)
- Xuan Ni
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Zhuang-zhuang Yang
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Ling-qun Ye
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Xing-long Han
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Dan-dan Zhao
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Feng-yue Ding
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Nan Ding
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Hong-chun Wu
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Miao Yu
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Guang-yin Xu
- grid.263761.70000 0001 0198 0694Institute of Neuroscience, Soochow University, Suzhou, 215123 China
| | - Zhen-ao Zhao
- grid.412026.30000 0004 1776 2036Institute of Microcirculation, Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, 075000 China
| | - Wei Lei
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
| | - Shi-jun Hu
- grid.263761.70000 0001 0198 0694Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, Collaborative Innovation Center of Hematology, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, 215000 China
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18
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Liu C, Bayado N, He D, Li J, Chen H, Li L, Li J, Long X, Du T, Tang J, Dang Y, Fan Z, Wang L, Yang PC. Therapeutic Applications of Extracellular Vesicles for Myocardial Repair. Front Cardiovasc Med 2021; 8:758050. [PMID: 34957249 PMCID: PMC8695616 DOI: 10.3389/fcvm.2021.758050] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2021] [Accepted: 11/10/2021] [Indexed: 12/12/2022] Open
Abstract
Cardiovascular disease is the leading cause of human death worldwide. Drug thrombolysis, percutaneous coronary intervention, coronary artery bypass grafting and other methods are used to restore blood perfusion for coronary artery stenosis and blockage. The treatments listed prolong lifespan, however, rate of mortality ultimately remains the same. This is due to the irreversible damage sustained by myocardium, in which millions of heart cells are lost during myocardial infarction. The lack of pragmatic methods of myocardial restoration remains the greatest challenge for effective treatment. Exosomes are small extracellular vesicles (EVs) actively secreted by all cell types that act as effective transmitters of biological signals which contribute to both reparative and pathological processes within the heart. Exosomes have become the focus of many researchers as a novel drug delivery system due to the advantages of low toxicity, little immunogenicity and good permeability. In this review, we discuss the progress and challenges of EVs in myocardial repair, and review the recent development of extracellular vesicle-loading systems based on their unique nanostructures and physiological functions, as well as the application of engineering modifications in the diagnosis and treatment of myocardial repair.
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Affiliation(s)
- Chunping Liu
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China.,State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macau, China
| | - Nathan Bayado
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
| | - Dongyue He
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jie Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Huiqi Chen
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Longmei Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jinhua Li
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Xinyao Long
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Tingting Du
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Jing Tang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Yue Dang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Zhijin Fan
- School of Medicine, South China University of Technology, Guangzhou, China
| | - Lei Wang
- State Key Laboratory of Dampness Syndrome of Chinese Medicine, The Second Affiliated Hospital of Guangzhou University of Chinese Medicine, Guangzhou, China
| | - Phillip C Yang
- Division of Cardiovascular Medicine, Department of Medicine, Stanford University School of Medicine, Stanford, CA, United States
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19
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
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20
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Chu X, Wang M, Qiu X, Huang Y, Li T, Otieno E, Li N, Luo L, Xiao X. Strategies for constructing pluripotent stem cell- and progenitor cell-derived three-dimensional cardiac micro-tissues. J Biomed Mater Res A 2021; 110:488-503. [PMID: 34397148 DOI: 10.1002/jbm.a.37298] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 07/31/2021] [Accepted: 08/04/2021] [Indexed: 12/15/2022]
Abstract
Three-dimensional (3D) cardiac micro-tissue is a promising model for simulating the structural and functional features of heart in vitro. This scientific achievement provides a platform for exploration about the mechanisms on the development, damage, and regeneration of tissue, hence, paving a way toward development of novel therapies for heart diseases. However, 3D micro-tissue technology is still in its infant stages faced with many challenges such as incompleteness of the tissue microarchitecture, loss of the resident immune cells, poor reproducibility, and deficiencies in continuously feeding the nutrients and removing wastes during micro-tissue culturing. There is an urgent need to optimize the construction of 3D cardiac micro-tissue and improve functions of the involved cells. Therefore, scaffolds and cell resources for building 3D cardiac micro-tissues, strategies for inducing the maturation and functionalization of pluripotent stem cell- or cardiac progenitor cell-derived cardiomyocytes, and the major challenges were reviewed in this writing to enable future fabrication of 3D cardiac micro-tissues or organoids for drug screening, disease modeling, regeneration treatment, and so on.
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Affiliation(s)
- Xinyue Chu
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Mingyu Wang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China.,Institute of Laboratory Animals Science, Chongqing Academy of Chinese Materia Medica, Chongqing, China
| | - Xiaoyan Qiu
- Department of Animal Husbandry Engineering, College of Animal Science and Technology, Southwest University, Chongqing, China
| | - Yun Huang
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Tong Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Edward Otieno
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Na Li
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Li Luo
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
| | - Xiong Xiao
- Department of Clinical Veterinary Medicine, College of Veterinary Medicine, Southwest University, Chongqing, China
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21
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Oh EJ, Gangadaran P, Rajendran RL, Kim HM, Oh JM, Choi KY, Chung HY, Ahn BC. Extracellular vesicles derived from fibroblasts promote wound healing by optimizing fibroblast and endothelial cellular functions. Stem Cells 2021; 39:266-279. [PMID: 33289943 DOI: 10.1002/stem.3310] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2020] [Accepted: 11/17/2020] [Indexed: 12/14/2022]
Abstract
Extracellular vesicles (EVs) have been exhibited as promising candidates for delivering endogenous therapeutic cargos for regenerative therapies. Fibroblasts could be candidate source cells for EVs, to investigate their therapeutic effects in wound healing. Here we demonstrated the isolation and characterization of fibroblast-derived (L929 cell line) EVs (L929-EVs). Furthermore, L929-EVs treatment showed pro-wound healing effects in vitro by enhancing proliferation, migration, and scarless wound healing related genes in fibroblast cells. L929-EVs treatment also enhanced the migration and tube formation of endothelial cells. The combination of L929-EVs with fibrin glue accelerated wound healing in the mouse skin wound model by enhancing collagen formation, collagen maturation, and blood vessels in the wounded skin. The role of fibroblast-derived EVs in wound healing could be an important phenomenon, and fibroblast-derived EVs could be harnessed for wound healing therapies.
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Affiliation(s)
- Eun Jung Oh
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Prakash Gangadaran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Ramya Lakshmi Rajendran
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Hyun Mi Kim
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Ji Min Oh
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Kang Young Choi
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
| | - Ho Yun Chung
- Department of Plastic and Reconstructive Surgery, CMRI, School of Medicine, Kyungpook National University, Kyungpook National University Hospital, Daegu, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
| | - Byeong-Cheol Ahn
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- BK21 FOUR KNU Convergence Educational Program of Biomedical Sciences for Creative Future Talents, School of Medicine, Kyungpook National University, Daegu, Republic of Korea
- Department of Nuclear Medicine, School of Medicine, Kyungpook National University Hospital, Daegu, Republic of Korea
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22
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Han X, Zhao ZA, Yan S, Lei W, Wu H, Lu XA, Chen Y, Li J, Wang Y, Yu M, Wang Y, Zheng Y, Wang H, Shen Z, Hu S. CXADR-like membrane protein protects against heart injury by preventing excessive pyroptosis after myocardial infarction. J Cell Mol Med 2020; 24:13775-13788. [PMID: 33084169 PMCID: PMC7753842 DOI: 10.1111/jcmm.15955] [Citation(s) in RCA: 23] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 08/24/2020] [Accepted: 09/18/2020] [Indexed: 12/17/2022] Open
Abstract
Myocardial infarction (MI) results in cardiomyocyte death and ultimately leads to heart failure. Pyroptosis is a type of the inflammatory programmed cell death that has been found in various diseased tissues. However, the role of pyroptosis in MI heart remains unknown. Here, we showed that CXADR‐like membrane protein (CLMP) was involved in pyroptosis in the mouse MI heart. Our data showed that CLMP was strongly expressed in fibroblasts of the infarcted mouse hearts. The Clmp+/− mice showed more serious myocardial fibrosis and ventricular dysfunction post‐MI than wild‐type (Clmp+/+) mice, indicating a protective effect of the fibroblast‐expressed CLMP against MI‐induced heart damage. Transcriptome analyses by RNA sequencing indicated that Il‐1β mRNA was significantly increased in the MI heart of Clmp+/− mouse, which indicated a more serious inflammatory response. Meanwhile, cleaved caspase‐1 and Gasdermin D were significantly increased in the Clmp+/− MI heart, which demonstrated enhanced pyroptosis in the Clmp knockdown heart. Further analysis revealed that the pyroptosis mainly occurred in cardiac fibroblasts (CFs). Compared to wild‐type fibroblasts, Clmp+/− CFs showed more serious pyroptosis and inflammatory after LPS plus nigericin treatment. Collectively, our results indicate that CLMP participates in the pyroptotic and inflammatory response of CFs in MI heart. We have provided a novel pyroptotic insight into the ischaemic heart, which might hold substantial potential for the treatment of MI.
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Affiliation(s)
- Xinglong Han
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Zhen-Ao Zhao
- Institute of Microcirculation & Department of Pathophysiology of Basic Medical College, Hebei North University, Zhangjiakou, China.,Hebei Key Laboratory of Critical Disease Mechanism and Intervention, Zhangjiakou, China
| | - Shiping Yan
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Wei Lei
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Hongchun Wu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Xing-Ai Lu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Yueqiu Chen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Jingjing Li
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Yaning Wang
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Miao Yu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Yongming Wang
- MOE Key Laboratory of Contemporary Anthropology at School of Life Sciences and Zhongshan Hospital, Fudan University, Shanghai, China
| | - Yufang Zheng
- Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Institute of Developmental Biology & Molecular Medicine, Fudan University, Shanghai, China
| | - Hongyan Wang
- Obstetrics and Gynecology Hospital, State Key Laboratory of Genetic Engineering at School of Life Sciences, Institute of Reproduction and Development, Fudan University, Shanghai, China.,Key Laboratory of Reproduction Regulation of NPFPC, Collaborative Innovation Center of Genetics and Development, Fudan University, Shanghai, China.,Children's Hospital of Fudan University, Shanghai, China
| | - Zhenya Shen
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
| | - Shijun Hu
- Department of Cardiovascular Surgery of the First Affiliated Hospital & Institute for Cardiovascular Science, State Key Laboratory of Radiation Medicine and Protection, Medical College, Soochow University, Suzhou, China
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23
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Lippi M, Stadiotti I, Pompilio G, Sommariva E. Human Cell Modeling for Cardiovascular Diseases. Int J Mol Sci 2020; 21:E6388. [PMID: 32887493 PMCID: PMC7503257 DOI: 10.3390/ijms21176388] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2020] [Revised: 08/28/2020] [Accepted: 08/31/2020] [Indexed: 11/17/2022] Open
Abstract
The availability of appropriate and reliable in vitro cell models recapitulating human cardiovascular diseases has been the aim of numerous researchers, in order to retrace pathologic phenotypes, elucidate molecular mechanisms, and discover therapies using simple and reproducible techniques. In the past years, several human cell types have been utilized for these goals, including heterologous systems, cardiovascular and non-cardiovascular primary cells, and embryonic stem cells. The introduction of induced pluripotent stem cells and their differentiation potential brought new prospects for large-scale cardiovascular experiments, bypassing ethical concerns of embryonic stem cells and providing an advanced tool for disease modeling, diagnosis, and therapy. Each model has its advantages and disadvantages in terms of accessibility, maintenance, throughput, physiological relevance, recapitulation of the disease. A higher level of complexity in diseases modeling has been achieved with multicellular co-cultures. Furthermore, the important progresses reached by bioengineering during the last years, together with the opportunities given by pluripotent stem cells, have allowed the generation of increasingly advanced in vitro three-dimensional tissue-like constructs mimicking in vivo physiology. This review provides an overview of the main cell models used in cardiovascular research, highlighting the pros and cons of each, and describing examples of practical applications in disease modeling.
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Affiliation(s)
- Melania Lippi
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (M.L.); (I.S.); (G.P.)
| | - Ilaria Stadiotti
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (M.L.); (I.S.); (G.P.)
| | - Giulio Pompilio
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (M.L.); (I.S.); (G.P.)
- Department of Clinical Sciences and Community Health, Università degli Studi di Milano, 20122 Milan, Italy
| | - Elena Sommariva
- Unit of Vascular Biology and Regenerative Medicine, Centro Cardiologico Monzino IRCCS, 20138 Milan, Italy; (M.L.); (I.S.); (G.P.)
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24
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Sung TC, Su HC, Ling QD, Kumar SS, Chang Y, Hsu ST, Higuchi A. Efficient differentiation of human pluripotent stem cells into cardiomyocytes on cell sorting thermoresponsive surface. Biomaterials 2020; 253:120060. [PMID: 32450407 DOI: 10.1016/j.biomaterials.2020.120060] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/29/2019] [Revised: 03/18/2020] [Accepted: 04/17/2020] [Indexed: 12/11/2022]
Abstract
The current differentiation process of human pluripotent stem cells (hPSCs) into cardiomyocytes to enhance the purity of hPSC-derived cardiomyocytes requires some purification processes, which are laborious processes. We developed cell sorting plates, which are prepared from coating thermoresponsive poly(N-isopropylacrylamide) and extracellular matrix proteins. After hPSCs were induced into cardiomyocytes on the thermoresponsive surface coated with laminin-521 for 15 days, the temperature of the cell culture plates was decreased to 8-9 °C to detach the cells partially from the thermoresponsive surface. The detached cells exhibited a higher cardiomyocyte marker of cTnT than the remaining cells on the thermoresponsive surface as well as the cardiomyocytes after purification using conventional cell selection. The detached cells expressed several cardiomyocyte markers, such as α-actinin, MLC2a and NKX2.5. This study suggested that the purification of hPSC-derived cardiomyocytes using cell sorting plates with the thermoresponsive surface is a promising method for the purification of hPSC-derived cardiomyocytes without conventional laborious processes.
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Affiliation(s)
- Tzu-Cheng Sung
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang, 325027, China; Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan, 32001, Taiwan
| | - Huan Chiao Su
- Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan, 32001, Taiwan
| | - Qing-Dong Ling
- Cathay Medical Research Institute, Cathay General Hospital, No. 32, Ln 160, Jian-Cheng Road, Hsi-Chi City, Taipei 221, Taiwan
| | - S Suresh Kumar
- Department of Medical Microbiology and Parasitology, Universiti Putra Malaysia, Serdang, 43400, Selangor, Malaysia
| | - Yung Chang
- Department of Chemical Engineering, R&D Center for Membrane Technology, Chung Yuan Christian University, 200, Chung-Bei Rd., Chungli, Taoyuan, 320, Taiwan
| | - Shih-Tien Hsu
- Department of Internal Medicine, Taiwan Landseed Hospital, 77, Kuangtai Road, Pingjen City, Taoyuan, 32405, Taiwan
| | - Akon Higuchi
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, No. 270, Xueyuan Road, Wenzhou, Zhejiang, 325027, China; Department of Chemical and Materials Engineering, National Central University, No. 300, Jhongda RD., Jhongli, Taoyuan, 32001, Taiwan; Department of Chemical Engineering, R&D Center for Membrane Technology, Chung Yuan Christian University, 200, Chung-Bei Rd., Chungli, Taoyuan, 320, Taiwan; Wenzhou Institute, University of Chinese Academy of Science, No. 16, Xinsan Road, Hi-tech Industry Park, Wenzhou, Zhejiang, China; Center for Emergent Matter Science, Riken, 2-1 Hirosawa, Wako, Saitama, 351-0198, Japan.
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25
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Liew LC, Ho BX, Soh BS. Mending a broken heart: current strategies and limitations of cell-based therapy. Stem Cell Res Ther 2020; 11:138. [PMID: 32216837 PMCID: PMC7098097 DOI: 10.1186/s13287-020-01648-0] [Citation(s) in RCA: 47] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2020] [Revised: 03/02/2020] [Accepted: 03/10/2020] [Indexed: 12/16/2022] Open
Abstract
The versatility of pluripotent stem cells, attributable to their unlimited self-renewal capacity and plasticity, has sparked a considerable interest for potential application in regenerative medicine. Over the past decade, the concept of replenishing the lost cardiomyocytes, the crux of the matter in ischemic heart disease, with pluripotent stem cell-derived cardiomyocytes (PSC-CM) has been validated with promising pre-clinical results. Nevertheless, clinical translation was hemmed in by limitations such as immature cardiac properties, long-term engraftment, graft-associated arrhythmias, immunogenicity, and risk of tumorigenicity. The continuous progress of stem cell-based cardiac therapy, incorporated with tissue engineering strategies and delivery of cardio-protective exosomes, provides an optimistic outlook on the development of curative treatment for heart failure. This review provides an overview and current status of stem cell-based therapy for heart regeneration, with particular focus on the use of PSC-CM. In addition, we also highlight the associated challenges in clinical application and discuss the potential strategies in developing successful cardiac-regenerative therapy.
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Affiliation(s)
- Lee Chuen Liew
- Disease Modeling and Therapeutics Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore, 138673, Singapore
| | - Beatrice Xuan Ho
- Disease Modeling and Therapeutics Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore, 138673, Singapore.,Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore
| | - Boon-Seng Soh
- Disease Modeling and Therapeutics Laboratory, A*STAR Institute of Molecular and Cell Biology, 61 Biopolis Drive Proteos, Singapore, 138673, Singapore. .,Department of Biological Sciences, National University of Singapore, Singapore, 117543, Singapore. .,Key Laboratory for Major Obstetric Diseases of Guangdong Province, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510150, China.
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