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Putra MA, Sandora N, Soetisna TW, Kusuma TR, Fitria NA, Karimah B, Noviana D, Gunanti, Busro PW, Supomo, Alwi I. Cocultured amniotic stem cells and cardiomyocytes in a 3-D acellular heart patch reduce the infarct size and left ventricle remodeling: promote angiogenesis in a porcine acute myocardial infarction model. J Cardiothorac Surg 2025; 20:229. [PMID: 40340905 PMCID: PMC12063456 DOI: 10.1186/s13019-025-03453-3] [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: 10/24/2024] [Accepted: 04/06/2025] [Indexed: 05/10/2025] Open
Abstract
BACKGROUND Acute myocardial infarction (AMI) induces significant myocardial damage, ultimately leading to heart failure as the surrounding healthy myocardial tissue undergoes progressive deterioration due to excessive mechanical stress. METHODS This study aimed to investigate myocardial regeneration in a porcine model of AMI using an acellular amniotic membrane with fibrin-termed an amnion bilayer (AB) or heart patch-as a cellular delivery system using porcine amniotic stem cells (pASCs) and autologous porcine cardiomyocytes (pCardios). Fifteen pigs (aged 2-4 months, weighing 50-60 kg) were randomly assigned to three experimental groups (n = 5): control group (AMI induction only), pASC group (pASC transplantation only), and coculture group (pASC and pCardio transplantation). AMI was induced via posterior left ventricular artery ligation and confirmed through standard biomarkers. After eight weeks, histological and molecular analyses were conducted to assess myocardial regeneration. RESULTS Improvement in regional wall motion abnormality (RWMA) was observed in 60% of the coculture group, 25% of the pASC group, and none in the control group. Histological analysis of the control group revealed extensive fibrosis with pronounced lipomatosis, particularly at the infarct center. In contrast, pASC and coculture groups exhibited minimal fibrotic scarring at both the infarct center and border regions. Immunofluorescence analysis demonstrated positive α-actinin expression in both the pASC and coculture groups, with the coculture group displaying sarcomeric structures-an organization absent in control group. RNA expression levels of key cardiomyogenic markers, including cardiac troponin T (cTnT), myosin heavy chain (MHC), and Nkx2.5, were significantly elevated in the treatment groups compared to the controls, with the coculture group exhibiting the highest MHC expression. The expression of c-Kit was also increased in both treatment groups relative to the control. Conversely, apoptotic markers p21 and Caspase-9 were highest in the control group, while coculture group exhibited the lowest p53 expression. CONCLUSION Epicardial transplantation of an acellular amniotic heart patch cocultured with cardiomyocytes and pASCs demonstrated superior cardiomyogenesis after eight weeks compared to pASC transplantation alone or control conditions. The coculture system was found to enhance the cardiac regeneration process, as evidenced by improved RWMA, distinct sarcomeric organization, reduced fibrotic scarring, and lower apoptotic gene expression.
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Affiliation(s)
- Muhammad Arza Putra
- Division of Thoracic, Cardiac and Vascular Surgery, Department of Surgery, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia.
| | - Normalina Sandora
- Indonesian Medical Education and Research Institute, Universitas Indonesia, Jakarta, 10430, Indonesia.
| | - Tri Wisesa Soetisna
- Division of Adult Cardiac Surgery, Harapan Kita National Cardiovascular Center, Jakarta, 11420, Indonesia
| | - Tyas Rahmah Kusuma
- Indonesian Medical Education and Research Institute, Universitas Indonesia, Jakarta, 10430, Indonesia
| | - Nur Amalina Fitria
- Indonesian Medical Education and Research Institute, Universitas Indonesia, Jakarta, 10430, Indonesia
| | - Benati Karimah
- Indonesian Medical Education and Research Institute, Universitas Indonesia, Jakarta, 10430, Indonesia
| | - Deni Noviana
- Division of Surgery and Radiology, School of Veterinary Medicine and Biomedical Sciences, IPB University, Bogor, 16680, Indonesia
| | - Gunanti
- Division of Surgery and Radiology, School of Veterinary Medicine and Biomedical Sciences, IPB University, Bogor, 16680, Indonesia
| | - Pribadi Wiranda Busro
- Division of Pediatric and Congenital Cardiac Surgery, Harapan Kita National Cardiovascular Center, Jakarta, 11420, Indonesia
| | - Supomo
- Division of Cardiothoracic Surgery, Department of Surgery, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, 55284, Indonesia
| | - Idrus Alwi
- Division of Cardiology, Department of Internal Medicine, Faculty of Medicine, Universitas Indonesia, Jakarta, 10430, Indonesia
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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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Szeliga A, Malcher A, Niwczyk O, Olszewska M, Kurpisz M, Meczekalski B, Adashi EY. Turner syndrome: the promise of fertility via stem cell technology. Hormones (Athens) 2025:10.1007/s42000-025-00647-1. [PMID: 40169532 DOI: 10.1007/s42000-025-00647-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2024] [Accepted: 03/19/2025] [Indexed: 04/03/2025]
Abstract
Turner syndrome (TS) is the most common female sex chromosome disorder, occurring in one out of every 2500 to 3000 live female births. It is caused by the partial or complete loss of one X chromosome. TS is associated with certain physical and medical features, including short stature, estrogen deficiency, delayed puberty, hypothyroidism, and congenital heart defects. The majority of women with TS are infertile as a result of gonadal dysgenesis and primary ovarian insufficiency causing hypergonadotropic hypogonadism. Several reproductive options are available for TS patients. The recent use of stem cells (SCs) was found to constitute a promising new alternative in cases of infertility treatment in this group. SCs are undifferentiated cells that exist in embryos, fetuses, and adults and that produce differentiated cells. They can be used in infertility treatment for ovarian regeneration and oocyte generation. However, additional studies scrutinizing their efficiency and safety are needed. In our review, we present reproductive options that are currently available for women with TS.
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Affiliation(s)
- Anna Szeliga
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Agnieszka Malcher
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Olga Niwczyk
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland
| | - Marta Olszewska
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
| | - Maciej Kurpisz
- Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland.
| | - Blazej Meczekalski
- Department of Gynecological Endocrinology, Poznan University of Medical Sciences, Poznan, Poland.
| | - Eli Y Adashi
- Department of Medical Science, Brown University, Providence, Rhode Island, USA
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Nair V, Demitri C, Thankam FG. Competitive signaling and cellular communications in myocardial infarction response. Mol Biol Rep 2025; 52:129. [PMID: 39820809 PMCID: PMC11739196 DOI: 10.1007/s11033-025-10236-5] [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: 08/08/2024] [Accepted: 01/07/2025] [Indexed: 01/19/2025]
Abstract
Cell communication and competition pathways are malleable to Myocardial Infarction (MI). Key signals, transcriptive regulators, and metabolites associated with apoptotic responses such as Myc, mTOR, and p53 are important players in the myocardium. The individual state of cardiomyocytes, fibroblasts, and macrophages in the heart tissue are adaptable in times of stress. The overlapping communication pathways of Wnt/β-catenin, Notch, and c-Kit exhibit the involvement of important factors in cell competition in the myocardium. Depending on the effects of these pathways on genetic expression and signal amplification, the proliferative capacities of the previously stated cells that make up the myocardium, amplify or diminish. This creates a distinct classification of "fit" and "unfit" cells. Beyond straightforward traits, the intricate metabolite interactions between neighboring cells unveil a complex battle. Strategic manipulation of these pathways holds translational promise for rapid cardiac recovery post-trauma.
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Affiliation(s)
- Vishnu Nair
- Department of Molecular, Cell, & Developmental Biology, University of California, Los Angeles, CA, 90095, USA
| | - Christian Demitri
- Department of Experimental Medicine, University of Salento, Lecce, 73100, Italy
| | - Finosh G Thankam
- Department of Translational Research, College of Osteopathic Medicine of the Pacific, Western University of Health Sciences, Pomona, CA, 91766-1854, USA.
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Ding JY, Meng TT, Du RL, Song XB, Li YX, Gao J, Ji R, He QY. Bibliometrics of trends in global research on the roles of stem cells in myocardial fibrosis therapy. World J Stem Cells 2024; 16:1086-1105. [PMID: 39734477 PMCID: PMC11669986 DOI: 10.4252/wjsc.v16.i12.1086] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2024] [Revised: 10/05/2024] [Accepted: 11/11/2024] [Indexed: 12/13/2024] Open
Abstract
BACKGROUND Myocardial fibrosis, a condition linked to several cardiovascular diseases, is associated with a poor prognosis. Stem cell therapy has emerged as a potential treatment option and the application of stem cell therapy has been studied extensively. However, a comprehensive bibliometric analysis of these studies has yet to be conducted. AIM To map thematic trends, analyze research hotspots, and project future directions of stem cell-based myocardial fibrosis therapy. METHODS We conducted a bibliometric and visual analysis of studies in the Web of Science Core Collection using VOSviewer and Microsoft Excel. The dataset included 1510 articles published between 2001 and 2024. Countries, organizations, authors, references, keywords, and co-citation networks were examined to identify evolving research trends. RESULTS Our findings revealed a steady increase in the number of publications, with a projected increase to over 200 publications annually by 2030. Initial research focused on stem cell-based therapy, particularly for myocardial infarction and heart failure. More recently, there has been a shift toward cell-free therapy, involving extracellular vesicles, exosomes, and microRNAs. Key research topics include angiogenesis, inflammation, apoptosis, autophagy, and oxidative stress. CONCLUSION This analysis highlights the evolution of stem cell therapies for myocardial fibrosis, with emerging interest in cell-free approaches. These results are expected to guide future scientific exploration and decision-making.
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Affiliation(s)
- Jing-Yi Ding
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Tian-Tian Meng
- Department of Rehabilitation, Dongfang Hospital, Beijing University of Chinese Medicine, Beijing 100071, China
| | - Ruo-Lin Du
- Department of Emergency Medicine, South Branch of Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Xin-Bin Song
- Department of Intensive Care Unit, Zhumadian Hospital of Traditional Chinese Medicine, Zhumadian 463000, Henan Province, China
| | - Yi-Xiang Li
- Department of Chinese Medicine, The Third People's Hospital of Henan Province, Zhengzhou 450000 Henan Province, China
| | - Jing Gao
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Ran Ji
- Department of Intensive Care Unit, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China
| | - Qing-Yong He
- Department of Cardiology, Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing 100053, China.
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Samundeshwari EL, Kattaru S, Kodavala S, Chandrasekhar C, Sarma PVGK. Differentiation ability of hematopoietic stem cells and mesenchymal stem cells isolated from human peripheral blood. Front Cell Dev Biol 2024; 12:1450543. [PMID: 39744010 PMCID: PMC11688275 DOI: 10.3389/fcell.2024.1450543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2024] [Accepted: 10/21/2024] [Indexed: 01/04/2025] Open
Abstract
Human hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) are the major stem cells of the bone marrow and are usually isolated from the peripheral blood. In the present study, we isolated these stem cells by an apheresis method from a donor who was administered granulocyte colony-stimulating factor (G-CSF). In vitro propagation of these stem cells showed a plastic-adherence property expressing CD73 and CD105 surface markers, which is a characteristic feature of MSCs. HSCs are non-adherent cells growing as a suspension culture, expressing CD150, CD133, CD34, and CD45 on their surface, which regulate the quiescence nature, and they derive energy from anaerobic glycolysis. The HSCs grow slowly compared to MSCs, are more viable, and survive for long periods under in vitro conditions, which are due to the expression of telomerase, BCL2, and Notch1 genes. The poor viability of MSCs in the culture due to the prominent expression of apoptotic genes BAX, caspase-3, and caspase-9 leads to rapid apoptosis. This was evident even in cells (astrocytes, osteocytes, and beta cells of the islets of Langerhans) differentiated from HSCs and MSCs, thus highlighting the importance of HSCs, the naive stem cells, in regeneration of tissues.
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Affiliation(s)
| | - Surekha Kattaru
- Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Sireesha Kodavala
- Department of Biotechnology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
| | - Chodimella Chandrasekhar
- Department of Hematology, Sri Venkateswara Institute of Medical Sciences, Tirupati, Andhra Pradesh, India
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Silva-Sousa T, Usuda JN, Al-Arawe N, Frias F, Hinterseher I, Catar R, Luecht C, Riesner K, Hackel A, Schimke LF, Dias HD, Filgueiras IS, Nakaya HI, Camara NOS, Fischer S, Riemekasten G, Ringdén O, Penack O, Winkler T, Duda G, Fonseca DLM, Cabral-Marques O, Moll G. The global evolution and impact of systems biology and artificial intelligence in stem cell research and therapeutics development: a scoping review. Stem Cells 2024; 42:929-944. [PMID: 39230167 DOI: 10.1093/stmcls/sxae054] [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: 06/13/2024] [Accepted: 08/07/2024] [Indexed: 09/05/2024]
Abstract
Advanced bioinformatics analysis, such as systems biology (SysBio) and artificial intelligence (AI) approaches, including machine learning (ML) and deep learning (DL), is increasingly present in stem cell (SC) research. An approximate timeline on these developments and their global impact is still lacking. We conducted a scoping review on the contribution of SysBio and AI analysis to SC research and therapy development based on literature published in PubMed between 2000 and 2024. We identified an 8 to 10-fold increase in research output related to all 3 search terms between 2000 and 2021, with a 10-fold increase in AI-related production since 2010. Use of SysBio and AI still predominates in preclinical basic research with increasing use in clinically oriented translational medicine since 2010. SysBio- and AI-related research was found all over the globe, with SysBio output led by the (US, n = 1487), (UK, n = 1094), Germany (n = 355), The Netherlands (n = 339), Russia (n = 215), and France (n = 149), while for AI-related research the US (n = 853) and UK (n = 258) take a strong lead, followed by Switzerland (n = 69), The Netherlands (n = 37), and Germany (n = 19). The US and UK are most active in SCs publications related to AI/ML and AI/DL. The prominent use of SysBio in ESC research was recently overtaken by prominent use of AI in iPSC and MSC research. This study reveals the global evolution and growing intersection among AI, SysBio, and SC research over the past 2 decades, with substantial growth in all 3 fields and exponential increases in AI-related research in the past decade.
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Affiliation(s)
- Thayna Silva-Sousa
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
| | - Júlia Nakanishi Usuda
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
| | - Nada Al-Arawe
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Hematology, Oncology, and Tumorimmunology, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Francisca Frias
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
| | - Irene Hinterseher
- Department of Vascular Surgery, Universitätsklinikum Ruppin-Brandenburg, Medizinische Hochschule Branderburg Theodor Fontane, 16816 Neuruppin, Germany
- Fakultät für Gesundheitswissenschaften Brandenburg, Gemeinsame Fakultät der Universität Potsdam, der Medizinischen Hochschule Brandenburg Theodor Fontane, und der Brandenburgischen Technischen Universität Cottbus-Senftenberg, 14476 Potsdam, Germany
- Vascular Surgery, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Rusan Catar
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Christian Luecht
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Katarina Riesner
- Department of Hematology, Oncology, and Tumorimmunology, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Alexander Hackel
- Clinic for Rheumatology and Clinical Immunology, University Medical Center Schleswig Holstein Campus Lübeck, 23538 Lübeck, Germany
| | - Lena F Schimke
- Department of Immunology, Institute of Biomedical Sciences, USP, SP, Brazil
| | - Haroldo Dutra Dias
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), USP, SP, Brazil
| | | | - Helder I Nakaya
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
- Department of Medicine, Division of Molecular Medicine, Laboratory of Medical Investigation 29, USP School of Medicine (USPM), São Paulo (SP), Brazil
| | - Niels Olsen Saraiva Camara
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
| | - Stefan Fischer
- Clinic for Rheumatology and Clinical Immunology, University Medical Center Schleswig Holstein Campus Lübeck, 23538 Lübeck, Germany
| | - Gabriela Riemekasten
- Clinic for Rheumatology and Clinical Immunology, University Medical Center Schleswig Holstein Campus Lübeck, 23538 Lübeck, Germany
| | - Olle Ringdén
- Division of Pediatrics, Department of CLINTEC, Karolinska Institutet, Stockholm, Sweden
| | - Olaf Penack
- Department of Hematology, Oncology, and Tumorimmunology, Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Tobias Winkler
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Georg Duda
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
| | - Dennyson Leandro M Fonseca
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), USP, SP, Brazil
| | - Otávio Cabral-Marques
- Department of Clinical and Toxicological Analyses, School of Pharmaceutical Sciences, University of São Paulo (USP), São Paulo (SP), Brazil
- Department of Immunology, Institute of Biomedical Sciences, USP, SP, Brazil
- Interunit Postgraduate Program on Bioinformatics, Institute of Mathematics and Statistics (IME), USP, SP, Brazil
- Department of Medicine, Division of Molecular Medicine, Laboratory of Medical Investigation 29, USP School of Medicine (USPM), São Paulo (SP), Brazil
- D'OR Institute Research and Education, SP, Brazil
| | - Guido Moll
- BIH Center for Regenerative Therapies (BCRT), Charité Universitätzsmedizin, corporate member of Freie Universität Berlin, Humboldt Universität zu Berlin, and Berlin Institute of Health (BIH), 10117 Berlin, Germany
- Julius Wolff Institute (JWI), Charité Universitätzsmedizin, 10117 Berlin, Germany
- Department of Nephrology and Internal Intensive Care Medicine, Charité Universitätzsmedizin, 10117 Berlin, Germany
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Jasper AA, Shah KH, Karim H, Gujral S, Miljkovic I, Rosano C, Barchowsky A, Sahu A. Regenerative rehabilitation measures to restore tissue function after arsenic exposure. CURRENT OPINION IN BIOMEDICAL ENGINEERING 2024; 30:100529. [PMID: 40191583 PMCID: PMC11970924 DOI: 10.1016/j.cobme.2024.100529] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/09/2025]
Abstract
Environmental exposure of arsenic impairs the cardiometabolic profile, skeletal muscle health, and neurological function. Such declining tissue health is observed as early as in one's childhood, where the exposure is prevalent, thereby accelerating the effect of time's arrow. Despite the known deleterious effects of arsenic exposure, there is a paucity of specific treatment plans for restoring tissue function in exposed individuals. In this review, we propose to harness the untapped potential of existing regenerative rehabilitation programs, such as stem cell therapeutics with rehabilitation, acellular therapeutics, and artificial intelligence/robotics technologies, to address this critical gap in environmental toxicology. With regenerative rehabilitation techniques showing promise in other injury paradigms, fostering collaboration between these scientific realms offers an effective means of mitigating the detrimental effects of arsenic on tissue function.
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Affiliation(s)
- Adam A Jasper
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, USA
| | - Kush H Shah
- The Lake Erie College of Osteopathic Medicine (LECOM), Erie, PA, USA
| | - Helmet Karim
- Department of Psychiatry, University of Pittsburgh, USA
- Department of Bioengineering, University of Pittsburgh, USA
| | - Swathi Gujral
- Department of Psychiatry, University of Pittsburgh, USA
| | - Iva Miljkovic
- Department of Epidemiology, University of Pittsburgh, USA
| | | | - Aaron Barchowsky
- Department of Environmental and Occupational Health, University of Pittsburgh, USA
| | - Amrita Sahu
- Department of Physical Medicine and Rehabilitation, University of Pittsburgh, USA
- Department of Environmental and Occupational Health, University of Pittsburgh, USA
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Garg P, Jamal F, Srivastava P. Comparative Transcriptomics Data Profiling Reveals E2F Targets as an Important Biological Pathway Overexpressed in Intellectual Disability Disorder. Bioinform Biol Insights 2024; 18:11779322231224665. [PMID: 38357659 PMCID: PMC10865946 DOI: 10.1177/11779322231224665] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Accepted: 12/15/2023] [Indexed: 02/16/2024] Open
Abstract
Intellectual disability (ID) is an early childhood neurodevelopmental disorder that is characterized by impaired intellectual functioning and adaptive behavior. It is one of the major concerns in the field of neurodevelopmental disorders across the globe. Diversified approaches have been put forward to overcome this problem. Among all these approaches, high throughput transcriptomic analysis has taken an important dimension. The identification of genes causing ID rapidly increased over the past 3 to 5 years owing to the use of sophisticated high throughput sequencing platforms. Early monitoring and preventions are much important for such disorder as their progression occurs during fetal development. This study is an attempt to identify differentially expressed genes (DEGs) and upregulated biological processes involved in development of ID patients through comparative analysis of available transcriptomics data. A total of 7 transcriptomic studies were retrieved from National Center for Biotechnology Information (NCBI) and were subjected to quality check and trimming prior to alignment. The normalization and differential expression analysis were carried out using DESeq2 and EdgeR packages of Rstudio to identify DEGs in ID. In progression of the study, functional enrichment analysis of the results obtained from both DESeq2 and EdgeR was done using gene set enrichment analysis (GSEA) tool to identify major upregulated biological processes involved in ID. Our findings concluded that monitoring the level of E2F targets, estrogen, and genes related to oxidative phosphorylation, DNA repair, and glycolysis during the developmental stage of an individual can help in the early detection of ID disorder.
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Affiliation(s)
- Prekshi Garg
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, India
| | - Farrukh Jamal
- Department of Biochemistry, Dr Rammanohar Lohia Avadh University, Ayodhya, India
| | - Prachi Srivastava
- Amity Institute of Biotechnology, Amity University Uttar Pradesh, Lucknow Campus, Lucknow, India
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10
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Bakbak E, Verma S, Krishnaraj A, Quan A, Wang CH, Pan Y, Puar P, Mason T, Verma R, Terenzi DC, Rotstein OD, Yan AT, Connelly KA, Teoh H, Mazer CD, Hess DA. Empagliflozin improves circulating vascular regenerative cell content in people without diabetes with risk factors for adverse cardiac remodeling. Am J Physiol Heart Circ Physiol 2023; 325:H1210-H1222. [PMID: 37773589 DOI: 10.1152/ajpheart.00141.2023] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2023] [Revised: 08/30/2023] [Accepted: 09/11/2023] [Indexed: 10/01/2023]
Abstract
Sodium glucose-cotransporter 2 (SGLT2) inhibitors have been reported to reduce cardiovascular events and heart failure in people with and without diabetes. These medications have been shown to counter regenerative cell exhaustion in the context of prevalent diabetes. This study sought to determine if empagliflozin attenuates regenerative cell exhaustion in people without diabetes. Peripheral blood mononuclear cells were collected at the baseline and 6-mo visits from individuals randomized to receive empagliflozin (10 mg/day) or placebo who were participating in the EMPA-HEART 2 CardioLink-7 trial. Precursor cell phenotypes were characterized by flow cytometry for cell-surface markers combined with high aldehyde dehydrogenase activity to identify precursor cell subsets with progenitor (ALDHhi) versus mature effector (ALDHlow) cell attributes. Samples from individuals assigned to empagliflozin (n = 25) and placebo (n = 21) were analyzed. At baseline, overall frequencies of primitive progenitor cells (ALDHhiSSClow), monocyte (ALDHhiSSCmid), and granulocyte (ALDHhiSSChi) precursor cells in both groups were similar. At 6 mo, participants randomized to empagliflozin demonstrated increased ALDHhiSSClowCD133+CD34+ proangiogenic cells (P = 0.048), elevated ALDHhiSSCmidCD163+ regenerative monocyte precursors (P = 0.012), and decreased ALDHhiSSCmidCD86 + CD163- proinflammatory monocyte (P = 0.011) polarization compared with placebo. Empagliflozin promoted the recovery of multiple circulating provascular cell subsets in people without diabetes suggesting that the cardiovascular benefits of SGLT2 inhibitors may be attributed in part to the attenuation of vascular regenerative cell exhaustion that is independent of diabetes status.NEW & NOTEWORTHY Using an aldehyde dehydrogenase (ALDH) activity-based flow cytometry assay, we found that empagliflozin treatment for 6 mo was associated with parallel increases in circulating vascular regenerative ALDHhi-CD34/CD133-coexpressing progenitors and decreased proinflammatory ALDHhi-CD14/CD86-coexpressing monocyte precursors in individuals without diabetes but with cardiovascular risk factors. The rejuvenation of the vascular regenerative cell reservoir may represent a mechanism via which sodium glucose-cotransporter 2 (SGLT2) inhibitors limit maladaptive repair and delay the development and progression of cardiovascular diseases.
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Affiliation(s)
- Ehab Bakbak
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
| | - Subodh Verma
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Aishwarya Krishnaraj
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
| | - Adrian Quan
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
| | - Chao-Hung Wang
- Division of Cardiology, Department of Internal Medicine, Heart Failure Research Center, Keelung Chang Gung Memorial Hospital, Keelung, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Yi Pan
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
| | - Pankaj Puar
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada
| | - Tamique Mason
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
| | - Raj Verma
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- School of Medicine, Royal College of Surgeons in Ireland, Dublin, Ireland
| | | | - Ori D Rotstein
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Department of Surgery, University of Toronto, Toronto, Ontario, Canada
- Division of General Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
| | - Andrew T Yan
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Division of Cardiology, St Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Kim A Connelly
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Division of Cardiology, St Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Department of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
| | - Hwee Teoh
- Division of Cardiac Surgery, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Division of Endocrinology and Metabolism, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
| | - C David Mazer
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Department of Physiology, University of Toronto, Toronto, Ontario, Canada
- Department of Anesthesia, St. Michael's Hospital of Unity Health Toronto, Toronto, Ontario, Canada
- Department of Anesthesiology and Pain Medicine, University of Toronto, Toronto, Ontario, Canada
| | - David A Hess
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science and Li Ka Shing Knowledge Institute of St Michael's Hospital, Toronto, Ontario, Canada
- Department of Physiology and Pharmacology, Western University, London, Ontario, Canada
- Molecular Medicine Research Laboratories, Robarts Research Institute, London, Ontario, Canada
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11
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Mahoney SA, Dey AK, Basisty N, Herman AB. Identification and functional analysis of senescent cells in the cardiovascular system using omics approaches. Am J Physiol Heart Circ Physiol 2023; 325:H1039-H1058. [PMID: 37656130 PMCID: PMC10908411 DOI: 10.1152/ajpheart.00352.2023] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 08/28/2023] [Accepted: 08/28/2023] [Indexed: 09/02/2023]
Abstract
Cardiovascular disease (CVD) is a leading cause of morbidity and mortality worldwide, and senescent cells have emerged as key contributors to its pathogenesis. Senescent cells exhibit cell cycle arrest and secrete a range of proinflammatory factors, termed the senescence-associated secretory phenotype (SASP), which promotes tissue dysfunction and exacerbates CVD progression. Omics technologies, specifically transcriptomics and proteomics, offer powerful tools to uncover and define the molecular signatures of senescent cells in cardiovascular tissue. By analyzing the comprehensive molecular profiles of senescent cells, omics approaches can identify specific genetic alterations, gene expression patterns, protein abundances, and metabolite levels associated with senescence in CVD. These omics-based discoveries provide insights into the mechanisms underlying senescence-induced cardiovascular damage, facilitating the development of novel diagnostic biomarkers and therapeutic targets. Furthermore, integration of multiple omics data sets enables a systems-level understanding of senescence in CVD, paving the way for precision medicine approaches to prevent or treat cardiovascular aging and its associated complications.
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Affiliation(s)
- Sophia A Mahoney
- Department of Integrative Physiology, University of Colorado at Boulder, Boulder, Colorado, United States
| | - Amit K Dey
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States
| | - Nathan Basisty
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States
| | - Allison B Herman
- Intramural Research Program, National Institute on Aging, National Institutes of Health, Baltimore, Maryland, United States
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12
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Schwarzkopf L, Büttner P, Scholtyssek K, Schröter T, Hiller R, Hindricks G, Bollmann A, Laufs U, Ueberham L. C-kit pos cells in the human left atrial appendage. Heliyon 2023; 9:e21268. [PMID: 37954289 PMCID: PMC10637945 DOI: 10.1016/j.heliyon.2023.e21268] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2023] [Revised: 10/09/2023] [Accepted: 10/18/2023] [Indexed: 11/14/2023] Open
Abstract
Background Subpopulations of myocardial c-kitpos cells have the ability to stimulate regeneration in ischemic heart disease by paracrine effects. The left atrial appendage (LAA), which is easy accessible during cardiac surgery, may represent a perfect source for c-kitpos cell extraction for autologous cell therapies in the living human. So far, frequency and distribution of c-kitpos cells in LAA are unknown. Methods LAAs of patients who underwent cardiac surgery due to coronary artery disease (coronary artery bypass graft, CABG), valvular heart disease or both and of two body donors were examined. Tissue was fixed in 4 % paraformaldehyde, embedded in paraffin, dissected in consecutive sections and stained for c-kitpos cells. In parallel, grade of fibrosis, amount of fat per section and cells positive for mast cell tryptase were examined. Results We collected 27 LAAs (37.0 % female, mean left ventricular ejection fraction 50.4 %, 63.0 % persistent atrial fibrillation (AF)). Most of the patients underwent combined CABG and valve surgery (51.9 %). C-kitpos cells were detected in 3 different regions: A) Attached to the epicardial fat layer, B) close to vascular structures and C) between cardiomyocytes. C-kitpos cells ranged from 0.05 c-kitpos cells per mm2 to 67.5 c-kitpos cells per mm2. We found no association between number of c-kitpos cells and type of AF, amount of fibrosis or amount of fat. Up to 72 % of c-kitpos cells also showed a positive staining for mast cell tryptase. Conclusion C-kitpos cells are frequent in LAAs of cardiovascular patients with a rather homogenous distribution throughout the LAA. The LAA can therefore be considered as a source for extraction of a reasonable quantity of autologous cardiac progenitor cells in the living human patient.
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Affiliation(s)
- Lea Schwarzkopf
- St. Elisabeth-Krankenhaus Leipzig, Department of Anaesthesiology, Leipzig, Germany
- German Heart Center Berlin, Department of Electrophysiology, Berlin, Germany
| | - Petra Büttner
- Heart Center Leipzig at University of Leipzig, Department of Cardiology, Leipzig, Germany
| | - Karl Scholtyssek
- German Heart Center Berlin, Department of Electrophysiology, Berlin, Germany
| | - Thomas Schröter
- Heart Center Leipzig at University of Leipzig, Department of Cardiac Surgery, Leipzig, Germany
| | - Ruth Hiller
- Insitut für Pathologie, University of Leipzig Medical Center, Leipzig, Germany
| | - Gerhard Hindricks
- German Heart Center Berlin, Department of Electrophysiology, Berlin, Germany
- Leipzig Heart Institute, Leipzig, Germany
| | - Andreas Bollmann
- German Heart Center Berlin, Department of Electrophysiology, Berlin, Germany
- Leipzig Heart Institute, Leipzig, Germany
| | - Ulrich Laufs
- Klinik und Poliklinik für Kardiologie, University of Leipzig Medical Center, Leipzig, Germany
| | - Laura Ueberham
- German Heart Center Berlin, Department of Electrophysiology, Berlin, Germany
- Leipzig Heart Institute, Leipzig, Germany
- Klinik und Poliklinik für Kardiologie, University of Leipzig Medical Center, Leipzig, Germany
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13
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Liu Y, Hu J, Wang W, Wang Q. MircroRNA-145 Attenuates Cardiac Fibrosis Via Regulating Mitogen-Activated Protein Kinase Kinase Kinase 3. Cardiovasc Drugs Ther 2023; 37:655-665. [PMID: 35416554 DOI: 10.1007/s10557-021-07312-w] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/29/2021] [Indexed: 12/20/2022]
Abstract
PURPOSE This study aimed to explore the effect of microRNA (miR)-145 on cardiac fibrosis in heart failure mice and its target. METHODS Experiments were carried out in mice receiving left coronary artery ligation, transverse aortic constriction (TAC), or angiotensin (Ang) II to trigger heart failure, and in cardiac fibroblasts (CFs) with Ang II-induced fibrosis. RESULTS The miR-145 levels were decreased in the mice hearts of heart failure induced by myocardial infarction (MI), TAC or Ang II infusion, and in the Ang II-treated CFs. The impaired cardiac function was ameliorated by miR-145 agomiR in MI mice. The increased fibrosis and the levels of collagen I, collagen III, and transforming growth factor-beta (TGF-β) in MI mice were inhibited by miR-145 agomiR or miR-145 transgene (TG). The agomiR of miR-145 also attenuated the increases of collagen I, collagen III, and TGF-β in Ang II-treated CFs. Bioinformatics analysis and luciferase reporter assays indicated that mitogen-activated protein kinase kinase kinase 3 (MAP3K3) was a direct target gene of miR-145. MAP3K3 expression was suppressed by MiR-145 in CFs, while the MAP3K3 over-expression reversed the inhibiting effects of miR-145 agomiR on the Ang II-induced increases of collagen I, collagen III, and TGF-β in CFs. CONCLUSION These results indicated that miR-145 upregulation could improve cardiac dysfunction and cardiac fibrosis by inhibiting MAP3K3 in heart failure. Thus, upregulating miR-145 or blocking MAP3K3 can be used to treat heart failure and cardiac fibrosis.
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Affiliation(s)
- Yun Liu
- Department of Intensive Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Jing Hu
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Weiwei Wang
- Department of Intensive Care Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Qian Wang
- Pediatric Department, Shanghai General Hospital, No.650 Xinsongjiang Road, Shanghai, 201600, Songjiang District, China.
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14
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Wolfien M, Ahmadi N, Fitzer K, Grummt S, Heine KL, Jung IC, Krefting D, Kühn A, Peng Y, Reinecke I, Scheel J, Schmidt T, Schmücker P, Schüttler C, Waltemath D, Zoch M, Sedlmayr M. Ten Topics to Get Started in Medical Informatics Research. J Med Internet Res 2023; 25:e45948. [PMID: 37486754 PMCID: PMC10407648 DOI: 10.2196/45948] [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: 01/23/2023] [Revised: 03/29/2023] [Accepted: 04/11/2023] [Indexed: 07/25/2023] Open
Abstract
The vast and heterogeneous data being constantly generated in clinics can provide great wealth for patients and research alike. The quickly evolving field of medical informatics research has contributed numerous concepts, algorithms, and standards to facilitate this development. However, these difficult relationships, complex terminologies, and multiple implementations can present obstacles for people who want to get active in the field. With a particular focus on medical informatics research conducted in Germany, we present in our Viewpoint a set of 10 important topics to improve the overall interdisciplinary communication between different stakeholders (eg, physicians, computational experts, experimentalists, students, patient representatives). This may lower the barriers to entry and offer a starting point for collaborations at different levels. The suggested topics are briefly introduced, then general best practice guidance is given, and further resources for in-depth reading or hands-on tutorials are recommended. In addition, the topics are set to cover current aspects and open research gaps of the medical informatics domain, including data regulations and concepts; data harmonization and processing; and data evaluation, visualization, and dissemination. In addition, we give an example on how these topics can be integrated in a medical informatics curriculum for higher education. By recognizing these topics, readers will be able to (1) set clinical and research data into the context of medical informatics, understanding what is possible to achieve with data or how data should be handled in terms of data privacy and storage; (2) distinguish current interoperability standards and obtain first insights into the processes leading to effective data transfer and analysis; and (3) value the use of newly developed technical approaches to utilize the full potential of clinical data.
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Affiliation(s)
- Markus Wolfien
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Scalable Data Analytics and Artificial Intelligence, Dresden, Germany
| | - Najia Ahmadi
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Kai Fitzer
- Core Unit Data Integration Center, University Medicine Greifswald, Greifswald, Germany
| | - Sophia Grummt
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Kilian-Ludwig Heine
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ian-C Jung
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Dagmar Krefting
- Department of Medical Informatics, University Medical Center, Goettingen, Germany
| | - Andreas Kühn
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Yuan Peng
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Ines Reinecke
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Julia Scheel
- Department of Systems Biology and Bioinformatics, University of Rostock, Rostock, Germany
| | - Tobias Schmidt
- Institute for Medical Informatics, University of Applied Sciences Mannheim, Mannheim, Germany
| | - Paul Schmücker
- Institute for Medical Informatics, University of Applied Sciences Mannheim, Mannheim, Germany
| | - Christina Schüttler
- Central Biobank Erlangen, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany
| | - Dagmar Waltemath
- Core Unit Data Integration Center, University Medicine Greifswald, Greifswald, Germany
- Department of Medical Informatics, University Medicine Greifswald, Greifswald, Germany
| | - Michele Zoch
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
| | - Martin Sedlmayr
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
- Center for Scalable Data Analytics and Artificial Intelligence, Dresden, Germany
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15
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Gaebel R, Lang C, Vasudevan P, Lührs L, de Carvalho KAT, Abdelwahid E, David R. New Approaches in Heart Research: Prevention Instead of Cardiomyoplasty? Int J Mol Sci 2023; 24:ijms24109017. [PMID: 37240361 DOI: 10.3390/ijms24109017] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 05/10/2023] [Accepted: 05/17/2023] [Indexed: 05/28/2023] Open
Abstract
Cardiovascular diseases are the leading cause of death in industrialized nations. Due to the high number of patients and expensive treatments, according to the Federal Statistical Office (2017) in Germany, cardiovascular diseases account for around 15% of total health costs. Advanced coronary artery disease is mainly the result of chronic disorders such as high blood pressure, diabetes, and dyslipidemia. In the modern obesogenic environment, many people are at greater risk of being overweight or obese. The hemodynamic load on the heart is influenced by extreme obesity, which often leads to myocardial infarction (MI), cardiac arrhythmias, and heart failure. In addition, obesity leads to a chronic inflammatory state and negatively affects the wound-healing process. It has been known for many years that lifestyle interventions such as exercise, healthy nutrition, and smoking cessation drastically reduce cardiovascular risk and have a preventive effect against disorders in the healing process. However, little is known about the underlying mechanisms, and there is significantly less high-quality evidence compared to pharmacological intervention studies. Due to the immense potential of prevention in heart research, the cardiologic societies are calling for research work to be intensified, from basic understanding to clinical application. The topicality and high relevance of this research area are also evident from the fact that in March 2018, a one-week conference on this topic with contributions from top international scientists took place as part of the renowned "Keystone Symposia" ("New Insights into the Biology of Exercise"). Consistent with the link between obesity, exercise, and cardiovascular disease, this review attempts to draw lessons from stem-cell transplantation and preventive exercise. The application of state-of-the-art techniques for transcriptome analysis has opened new avenues for tailoring targeted interventions to very individual risk factors.
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Affiliation(s)
- Ralf Gaebel
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Cajetan Lang
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Praveen Vasudevan
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Larissa Lührs
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, Pelé Pequeno Prίncipe Research Institute & Pequeno Prίncipe Faculties, Ave. Silva Jardim, P.O. Box 80240-020, Curitiba 1632, Brazil
| | - Katherine Athayde Teixeira de Carvalho
- Advanced Therapy and Cellular Biotechnology in Regenerative Medicine Department, Pelé Pequeno Prίncipe Research Institute & Pequeno Prίncipe Faculties, Ave. Silva Jardim, P.O. Box 80240-020, Curitiba 1632, Brazil
| | - Eltyeb Abdelwahid
- Feinberg School of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University, Chicago, IL 60611, USA
| | - Robert David
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
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16
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Pushpakumar S, Singh M, Zheng Y, Akinterinwa OE, Mokshagundam SPL, Sen U, Kalra DK, Tyagi SC. Renal Denervation Helps Preserve the Ejection Fraction by Preserving Endocardial-Endothelial Function during Heart Failure. Int J Mol Sci 2023; 24:ijms24087302. [PMID: 37108465 PMCID: PMC10139195 DOI: 10.3390/ijms24087302] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 04/12/2023] [Accepted: 04/13/2023] [Indexed: 04/29/2023] Open
Abstract
Renal denervation (RDN) protects against hypertension, hypertrophy, and heart failure (HF); however, it is not clear whether RDN preserves ejection fraction (EF) during heart failure (HFpEF). To test this hypothesis, we simulated a chronic congestive cardiopulmonary heart failure (CHF) phenotype by creating an aorta-vena cava fistula (AVF) in the C57BL/6J wild type (WT) mice. Briefly, there are four ways to create an experimental CHF: (1) myocardial infarction (MI), which is basically ligating the coronary artery by instrumenting and injuring the heart; (2) trans-aortic constriction (TAC) method, which mimics the systematic hypertension, but again constricts the aorta on top of the heart and, in fact, exposes the heart; (3) acquired CHF condition, promoted by dietary factors, diabetes, salt, diet, etc., but is multifactorial in nature; and finally, (4) the AVF, which remains the only one wherein AVF is created ~1 cm below the kidneys in which the aorta and vena cava share the common middle-wall. By creating the AVF fistula, the red blood contents enter the vena cava without an injury to the cardiac tissue. This model mimics or simulates the CHF phenotype, for example, during aging wherein with advancing age, the preload volume keeps increasing beyond the level that the aging heart can pump out due to the weakened cardiac myocytes. Furthermore, this procedure also involves the right ventricle to lung to left ventricle flow, thus creating an ideal condition for congestion. The heart in AVF transitions from preserved to reduced EF (i.e., HFpEF to HFrEF). In fact, there are more models of volume overload, such as the pacing-induced and mitral valve regurgitation, but these are also injurious models in nature. Our laboratory is one of the first laboratories to create and study the AVF phenotype in the animals. The RDN was created by treating the cleaned bilateral renal artery. After 6 weeks, blood, heart, and renal samples were analyzed for exosome, cardiac regeneration markers, and the renal cortex proteinases. Cardiac function was analyzed by echocardiogram (ECHO) procedure. The fibrosis was analyzed with a trichrome staining method. The results suggested that there was a robust increase in the exosomes' level in AVF blood, suggesting a compensatory systemic response during AVF-CHF. During AVF, there was no change in the cardiac eNOS, Wnt1, or β-catenin; however, during RDN, there were robust increases in the levels of eNOS, Wnt1, and β-catenin compared to the sham group. As expected in HFpEF, there was perivascular fibrosis, hypertrophy, and pEF. Interestingly, increased levels of eNOS suggested that despite fibrosis, the NO generation was higher and that it most likely contributed to pEF during HF. The RDN intervention revealed an increase in renal cortical caspase 8 and a decrease in caspase 9. Since caspase 8 is protective and caspase 9 is apoptotic, we suggest that RDN protects against the renal stress and apoptosis. It should be noted that others have demonstrated a role of vascular endothelium in preserving the ejection by cell therapy intervention. In the light of foregoing evidence, our findings also suggest that RDN is cardioprotective during HFpEF via preservation of the eNOS and accompanied endocardial-endothelial function.
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Affiliation(s)
- Sathnur Pushpakumar
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Mahavir Singh
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Yuting Zheng
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Oluwaseun E Akinterinwa
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Sri Prakash L Mokshagundam
- Division of Endocrinology, Metabolism and Diabetes and Robley Rex VA Medical Center, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Utpal Sen
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
| | - Dinesh K Kalra
- Division of Cardiovascular Medicine, University of Louisville School of Medicine, Louisville, KY 40202, USA
| | - Suresh C Tyagi
- Department of Physiology, School of Medicine, University of Louisville, Louisville, KY 40202, USA
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17
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Scafa Udriște A, Niculescu AG, Iliuță L, Bajeu T, Georgescu A, Grumezescu AM, Bădilă E. Progress in Biomaterials for Cardiac Tissue Engineering and Regeneration. Polymers (Basel) 2023; 15:polym15051177. [PMID: 36904419 PMCID: PMC10007484 DOI: 10.3390/polym15051177] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/16/2023] [Accepted: 02/22/2023] [Indexed: 03/02/2023] Open
Abstract
Cardiovascular diseases are one of the leading global causes of morbidity and mortality, posing considerable health and economic burden on patients and medical systems worldwide. This phenomenon is attributed to two main motives: poor regeneration capacity of adult cardiac tissues and insufficient therapeutic options. Thus, the context calls for upgrading treatments to deliver better outcomes. In this respect, recent research has approached the topic from an interdisciplinary perspective. Combining the advances encountered in chemistry, biology, material science, medicine, and nanotechnology, performant biomaterial-based structures have been created to carry different cells and bioactive molecules for repairing and restoring heart tissues. In this regard, this paper aims to present the advantages of biomaterial-based approaches for cardiac tissue engineering and regeneration, focusing on four main strategies: cardiac patches, injectable hydrogels, extracellular vesicles, and scaffolds and reviewing the most recent developments in these fields.
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Affiliation(s)
- Alexandru Scafa Udriște
- Department 4 Cardio-Thoracic Pathology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Adelina-Gabriela Niculescu
- Research Institute of the University of Bucharest—ICUB, University of Bucharest, 050657 Bucharest, Romania
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Politehnica University of Bucharest, 011061 Bucharest, Romania
| | - Luminița Iliuță
- Department 4 Cardio-Thoracic Pathology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Teodor Bajeu
- Department 4 Cardio-Thoracic Pathology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
| | - Adriana Georgescu
- Pathophysiology and Pharmacology Department, Institute of Cellular Biology and Pathology “Nicolae Simionescu” of the Romanian Academy, 050568 Bucharest, Romania
| | - Alexandru Mihai Grumezescu
- Research Institute of the University of Bucharest—ICUB, University of Bucharest, 050657 Bucharest, Romania
- Department of Science and Engineering of Oxide Materials and Nanomaterials, Politehnica University of Bucharest, 011061 Bucharest, Romania
- Academy of Romanian Scientists, Ilfov No. 3, 050044 Bucharest, Romania
- Correspondence:
| | - Elisabeta Bădilă
- Department 4 Cardio-Thoracic Pathology, “Carol Davila” University of Medicine and Pharmacy, 050474 Bucharest, Romania
- Cardiology Department, Colentina Clinical Hospital, 020125 Bucharest, Romania
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18
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Paracrine-mediated rejuvenation of aged mesenchymal stem cells is associated with downregulation of the autophagy-lysosomal pathway. NPJ AGING 2022; 8:10. [PMID: 35927427 PMCID: PMC9293998 DOI: 10.1038/s41514-022-00091-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 06/30/2022] [Indexed: 12/02/2022]
Abstract
Age-related differences in stem-cell potency contribute to variable outcomes in clinical stem cell trials. To help understand the effect of age on stem cell potency, bone marrow-derived mesenchymal stem cells (MSCs) were isolated from young (6 weeks) and old (18–24 months) mice. HUVEC tubule formation (TF) induced by the old and young MSCs and ELISA of conditioned media were compared to one another, and to old MSCs after 7 d in indirect co-culture with young MSCs. Old MSCs induced less TF than did young (1.56 ± 0.11 vs 2.38 ± 0.17, p = 0.0003) and released lower amounts of VEGF (p = 0.009) and IGF1 (p = 0.037). After 7 d in co-culture with young MSCs, TF by the old MSCs significantly improved (to 2.09 ± 0.18 from 1.56 ± 0.11; p = 0.013), and was no longer different compared to TF from young MSCs (2.09 ± 0.18 vs 2.38 ± 0.17; p = 0.27). RNA seq of old MSCs, young MSCs, and old MSCs following co-culture with young MSCs revealed that the age-related differences were broadly modified by co-culture, with the most significant changes associated with lysosomal pathways. These results indicate that the age-associated decreased paracrine-mediated effects of old MSCs are improved following indirect co-culture with young MSC. The observed effect is associated with broad transcriptional modification, suggesting potential targets to both assess and improve the therapeutic potency of stem cells from older patients.
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19
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Ahmad B, Skorska A, Wolfien M, Sadraddin H, Lemcke H, Vasudevan P, Wolkenhauer O, Steinhoff G, David R, Gaebel R. The Effects of Hypoxic Preconditioned Murine Mesenchymal Stem Cells on Post-Infarct Arrhythmias in the Mouse Model. Int J Mol Sci 2022; 23:ijms23168843. [PMID: 36012110 PMCID: PMC9408396 DOI: 10.3390/ijms23168843] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 08/04/2022] [Accepted: 08/05/2022] [Indexed: 11/16/2022] Open
Abstract
Ventricular arrhythmias associated with myocardial infarction (MI) have a significant impact on mortality in patients following heart attack. Therefore, targeted reduction of arrhythmia represents a therapeutic approach for the prevention and treatment of severe events after infarction. Recent research transplanting mesenchymal stem cells (MSC) showed their potential in MI therapy. Our study aimed to investigate the effects of MSC injection on post-infarction arrhythmia. We used our murine double infarction model, which we previously established, to more closely mimic the clinical situation and intramyocardially injected hypoxic pre-conditioned murine MSC to the infarction border. Thereafter, various types of arrhythmias were recorded and analyzed. We observed a homogenous distribution of all types of arrhythmias after the first infarction, without any significant differences between the groups. Yet, MSC therapy after double infarction led to a highly significant reduction in simple and complex arrhythmias. Moreover, RNA-sequencing of samples from stem cell treated mice after re-infarction demonstrated a significant decline in most arrhythmias with reduced inflammatory pathways. Additionally, following stem-cell therapy we found numerous highly expressed genes to be either linked to lowering the risk of heart failure, cardiomyopathy or sudden cardiac death. Moreover, genes known to be associated with arrhythmogenesis and key mutations underlying arrhythmias were downregulated. In summary, our stem-cell therapy led to a reduction in cardiac arrhythmias after MI and showed a downregulation of already established inflammatory pathways. Furthermore, our study reveals gene regulation pathways that have a potentially direct influence on arrhythmogenesis after myocardial infarction.
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Affiliation(s)
- Beschan Ahmad
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Anna Skorska
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Markus Wolfien
- Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany
- Institute for Medical Informatics and Biometry, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, 01307 Dresden, Germany
| | - Haval Sadraddin
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Heiko Lemcke
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Praveen Vasudevan
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Olaf Wolkenhauer
- Department of Systems Biology and Bioinformatics, University of Rostock, 18051 Rostock, Germany
| | - Gustav Steinhoff
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
| | - Robert David
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
- Correspondence: ; Tel.: +49-381-4988973; Fax: +49-381-4988970
| | - Ralf Gaebel
- Department of Cardiac Surgery, Rostock University Medical Center, 18057 Rostock, Germany
- Department of Life, Light & Matter, Interdisciplinary Faculty, Rostock University, 18059 Rostock, Germany
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20
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Xu Z, Neuber S, Nazari-Shafti T, Liu Z, Dong F, Stamm C. Impact of procedural variability and study design quality on the efficacy of cell-based therapies for heart failure - a meta-analysis. PLoS One 2022; 17:e0261462. [PMID: 34986181 PMCID: PMC8730409 DOI: 10.1371/journal.pone.0261462] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2021] [Accepted: 12/02/2021] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND Cell-based therapy has long been considered a promising strategy for the treatment of heart failure (HF). However, its effectiveness in the clinical setting is now doubted. Because previous meta-analyses provided conflicting results, we sought to review all available data focusing on cell type and trial design. METHODS AND FINDINGS The electronic databases PubMed, Cochrane library, ClinicalTrials.gov, and EudraCT were searched for randomized controlled trials (RCTs) utilizing cell therapy for HF patients from January 1, 2000 to December 31, 2020. Forty-three RCTs with 2855 participants were identified. The quality of the reported study design was assessed by evaluating the risk-of-bias (ROB). Primary outcomes were defined as mortality rate and left ventricular ejection fraction (LVEF) change from baseline. Secondary outcomes included both heart function data and clinical symptoms/events. Between-study heterogeneity was assessed using the I2 index. Subgroup analysis was performed based on HF type, cell source, cell origin, cell type, cell processing, type of surgical intervention, cell delivery routes, cell dose, and follow-up duration. Only 10 of the 43 studies had a low ROB for all method- and outcome parameters. A higher ROB was associated with a greater increase in LVEF. Overall, there was no impact on mortality for up to 12 months follow-up, and a clinically irrelevant average LVEF increase by LVEF (2.4%, 95% CI = 0.75-4.05, p = 0.004). Freshly isolated, primary cells tended to produce better outcomes than cultured cell products, but there was no clear impact of the cell source tissue, bone marrow cell phenotype or cell chricdose (raw or normalized for CD34+ cells). A meaningful increase in LVEF was only observed when cell therapy was combined with myocardial revascularization. CONCLUSIONS The published results suggest a small increase in LVEF following cell therapy for heart failure, but publication bias and methodologic shortcomings need to be taken into account. Given that cardiac cell therapy has now been pursued for 20 years without real progress, further efforts should not be made. STUDY REGISTRY NUMBER This meta-analysis is registered at the international prospective register of systematic reviews, number CRD42019118872.
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Affiliation(s)
- Zhiyi Xu
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Sebastian Neuber
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
| | - Timo Nazari-Shafti
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
- Berlin Institute of Health at Charité, Universitätsmedizin Berlin, Berlin, Germany
| | - Zihou Liu
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
| | - Fengquan Dong
- Department of Cardiology, Shenzhen University General Hospital, Shenzhen, Guangdong, China
| | - Christof Stamm
- Berlin Institute of Health Center for Regenerative Therapies, Charité–Universitätsmedizin Berlin, Berlin, Germany
- Department of Cardiothoracic and Vascular Surgery, German Heart Center Berlin, Berlin, Germany
- German Centre for Cardiovascular Research, Partner Site Berlin, Berlin, Germany
- Helmholtz Zentrum Geesthacht, Institut für Aktive Polymere, Teltow, Germany
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21
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Salybekov AA, Wolfien M, Kobayashi S, Steinhoff G, Asahara T. Personalized Cell Therapy for Patients with Peripheral Arterial Diseases in the Context of Genetic Alterations: Artificial Intelligence-Based Responder and Non-Responder Prediction. Cells 2021; 10:3266. [PMID: 34943774 PMCID: PMC8699290 DOI: 10.3390/cells10123266] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Revised: 11/15/2021] [Accepted: 11/17/2021] [Indexed: 01/14/2023] Open
Abstract
Stem/progenitor cell transplantation is a potential novel therapeutic strategy to induce angiogenesis in ischemic tissue, which can prevent major amputation in patients with advanced peripheral artery disease (PAD). Thus, clinicians can use cell therapies worldwide to treat PAD. However, some cell therapy studies did not report beneficial outcomes. Clinical researchers have suggested that classical risk factors and comorbidities may adversely affect the efficacy of cell therapy. Some studies have indicated that the response to stem cell therapy varies among patients, even in those harboring limited risk factors. This suggests the role of undetermined risk factors, including genetic alterations, somatic mutations, and clonal hematopoiesis. Personalized stem cell-based therapy can be developed by analyzing individual risk factors. These approaches must consider several clinical biomarkers and perform studies (such as genome-wide association studies (GWAS)) on disease-related genetic traits and integrate the findings with those of transcriptome-wide association studies (TWAS) and whole-genome sequencing in PAD. Additional unbiased analyses with state-of-the-art computational methods, such as machine learning-based patient stratification, are suited for predictions in clinical investigations. The integration of these complex approaches into a unified analysis procedure for the identification of responders and non-responders before stem cell therapy, which can decrease treatment expenditure, is a major challenge for increasing the efficacy of therapies.
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Affiliation(s)
- Amankeldi A. Salybekov
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan;
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan
| | - Markus Wolfien
- Department of Systems Biology and Bioinformatics, University of Rostock, Ulmenstrasse 69, 18057 Rostock, Germany;
| | - Shuzo Kobayashi
- Kidney Disease and Transplant Center, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan;
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan
| | - Gustav Steinhoff
- Department of Cardiac Surgery, Rostock University Medical Center, 18059 Rostock, Germany;
- Department Life, Light & Matter, University of Rostock, 18057 Rostock, Germany
| | - Takayuki Asahara
- Shonan Research Institute of Innovative Medicine, Shonan Kamakura General Hospital, 1-1370 Okamoto, Kamakura 2478533, Japan
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22
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Huang K, Xiao C, Glass LM, Critchlow CW, Gibson G, Sun J. Machine learning applications for therapeutic tasks with genomics data. PATTERNS (NEW YORK, N.Y.) 2021; 2:100328. [PMID: 34693370 PMCID: PMC8515011 DOI: 10.1016/j.patter.2021.100328] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
Thanks to the increasing availability of genomics and other biomedical data, many machine learning algorithms have been proposed for a wide range of therapeutic discovery and development tasks. In this survey, we review the literature on machine learning applications for genomics through the lens of therapeutic development. We investigate the interplay among genomics, compounds, proteins, electronic health records, cellular images, and clinical texts. We identify 22 machine learning in genomics applications that span the whole therapeutics pipeline, from discovering novel targets, personalizing medicine, developing gene-editing tools, all the way to facilitating clinical trials and post-market studies. We also pinpoint seven key challenges in this field with potentials for expansion and impact. This survey examines recent research at the intersection of machine learning, genomics, and therapeutic development.
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Affiliation(s)
- Kexin Huang
- Department of Computer Science, Stanford University, Stanford, CA 94305, USA
| | - Cao Xiao
- Amplitude, San Francisco, CA 94105, USA
| | - Lucas M. Glass
- Analytics Center of Excellence, IQVIA, Cambridge, MA 02139, USA
| | | | - Greg Gibson
- Center for Integrative Genomics, Georgia Institute of Technology, Atlanta, GA 30332, USA
| | - Jimeng Sun
- Computer Science Department and Carle's Illinois College of Medicine, University of Illinois at Urbana-Champaign, Urbana, IL 61820, USA
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23
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Evens L, Beliën H, D’Haese S, Haesen S, Verboven M, Rummens JL, Bronckaers A, Hendrikx M, Deluyker D, Bito V. Combinational Therapy of Cardiac Atrial Appendage Stem Cells and Pyridoxamine: The Road to Cardiac Repair? Int J Mol Sci 2021; 22:ijms22179266. [PMID: 34502175 PMCID: PMC8431115 DOI: 10.3390/ijms22179266] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Revised: 08/24/2021] [Accepted: 08/25/2021] [Indexed: 12/04/2022] Open
Abstract
Myocardial infarction (MI) occurs when the coronary blood supply is interrupted. As a consequence, cardiomyocytes are irreversibly damaged and lost. Unfortunately, current therapies for MI are unable to prevent progression towards heart failure. As the renewal rate of cardiomyocytes is minimal, the optimal treatment should achieve effective cardiac regeneration, possibly with stem cells transplantation. In that context, our research group identified the cardiac atrial appendage stem cells (CASCs) as a new cellular therapy. However, CASCs are transplanted into a hostile environment, with elevated levels of advanced glycation end products (AGEs), which may affect their regenerative potential. In this study, we hypothesize that pyridoxamine (PM), a vitamin B6 derivative, could further enhance the regenerative capacities of CASCs transplanted after MI by reducing AGEs’ formation. Methods and Results: MI was induced in rats by ligation of the left anterior descending artery. Animals were assigned to either no therapy (MI), CASCs transplantation (MI + CASCs), or CASCs transplantation supplemented with PM treatment (MI + CASCs + PM). Four weeks post-surgery, global cardiac function and infarct size were improved upon CASCs transplantation. Interstitial collagen deposition, evaluated on cryosections, was decreased in the MI animals transplanted with CASCs. Contractile properties of resident left ventricular cardiomyocytes were assessed by unloaded cell shortening. CASCs transplantation prevented cardiomyocyte shortening deterioration. Even if PM significantly reduced cardiac levels of AGEs, cardiac outcome was not further improved. Conclusion: Limiting AGEs’ formation with PM during an ischemic injury in vivo did not further enhance the improved cardiac phenotype obtained with CASCs transplantation. Whether AGEs play an important deleterious role in the setting of stem cell therapy after MI warrants further examination.
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Affiliation(s)
- Lize Evens
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Hanne Beliën
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Sarah D’Haese
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Sibren Haesen
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Maxim Verboven
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Jean-Luc Rummens
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
- UHasselt—Hasselt University, Faculty of Medicine and Life Sciences, Agoralaan, 3590 Diepenbeek, Belgium
| | - Annelies Bronckaers
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Marc Hendrikx
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Dorien Deluyker
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
| | - Virginie Bito
- UHasselt—Hasselt University, BIOMED—Biomedical Research Institute, Agoralaan, 3590 Diepenbeek, Belgium; (L.E.); (H.B.); (S.D.); (S.H.); (M.V.); (J.-L.R.); (A.B.); (M.H.); (D.D.)
- Correspondence: ; Tel.: +32-11269285
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24
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Deciphering the Code: Stem Cell-Immune Function and Cardiac Regeneration. Cells 2021; 10:cells10030592. [PMID: 33800252 PMCID: PMC8001404 DOI: 10.3390/cells10030592] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2021] [Accepted: 03/05/2021] [Indexed: 11/21/2022] Open
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25
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Competitive sgRNA Screen Identifies p38 MAPK as a Druggable Target to Improve HSPC Engraftment. Cells 2020; 9:cells9102194. [PMID: 33003308 PMCID: PMC7600420 DOI: 10.3390/cells9102194] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2020] [Revised: 09/22/2020] [Accepted: 09/26/2020] [Indexed: 12/28/2022] Open
Abstract
Previous gene therapy trials for X-linked chronic granulomatous disease (X-CGD) lacked long-term engraftment of corrected hematopoietic stem and progenitor cells (HSPCs). Chronic inflammation and high levels of interleukin-1 beta (IL1B) might have caused aberrant cell cycling in X-CGD HSPCs with a concurrent loss of their long-term repopulating potential. Thus, we performed a targeted CRISPR-Cas9-based sgRNA screen to identify candidate genes that counteract the decreased repopulating capacity of HSPCs during gene therapy. The candidates were validated in a competitive transplantation assay and tested in a disease context using IL1B-challenged or X-CGD HSPCs. The sgRNA screen identified Mapk14 (p38) as a potential target to increase HSPC engraftment. Knockout of p38 prior to transplantation was sufficient to induce a selective advantage. Inhibition of p38 increased expression of the HSC homing factor CXCR4 and reduced apoptosis and proliferation in HSPCs. For potential clinical translation, treatment of IL1B-challenged or X-CGD HSPCs with a p38 inhibitor led to a 1.5-fold increase of donor cell engraftment. In summary, our findings demonstrate that p38 may serve as a potential druggable target to restore engraftment of HSPCs in the context of X-CGD gene therapy.
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26
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Firouzi F, Sussman MA. Blood speaks: Personalised medicine profiling for heart failure patients. EBioMedicine 2020; 58:102900. [PMID: 32711252 PMCID: PMC7387776 DOI: 10.1016/j.ebiom.2020.102900] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 07/02/2020] [Indexed: 01/06/2023] Open
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