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Cui X, Guo J, Yuan P, Dai Y, Du P, Yu F, Sun Z, Zhang J, Cheng K, Tang J. Bioderived Nanoparticles for Cardiac Repair. ACS NANO 2024; 18:24622-24649. [PMID: 39185722 DOI: 10.1021/acsnano.3c07878] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 08/27/2024]
Abstract
Biobased therapy represents a promising strategy for myocardial repair. However, the limitations of using live cells, including the risk of immunogenicity of allogeneic cells and inconsistent therapeutic efficacy of autologous cells together with low stability, result in an unsatisfactory clinical outcomes. Therefore, cell-free strategies for cardiac tissue repair have been proposed as alternative strategies. Cell-free strategies, primarily based on the paracrine effects of cellular therapy, have demonstrated their potential to inhibit apoptosis, reduce inflammation, and promote on-site cell migration and proliferation, as well as angiogenesis, after an infarction and have been explored preclinically and clinically. Among various cell-free modalities, bioderived nanoparticles, including adeno-associated virus (AAV), extracellular vesicles, cell membrane-coated nanoparticles, and exosome-mimetic nanovesicles, have emerged as promising strategies due to their improved biological function and therapeutic effect. The main focus of this review is the development of existing cellular nanoparticles and their fundamental working mechanisms, as well as the challenges and opportunities. The key processes and requirements for cardiac tissue repair are summarized first. Various cellular nanoparticle modalities are further highlighted, together with their advantages and limitations. Finally, we discuss various delivery approaches that offer potential pathways for researchers and clinicians to translate cell-free strategies for cardiac tissue repair into clinical practice.
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Affiliation(s)
- Xiaolin Cui
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Jiacheng Guo
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Peiyu Yuan
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Yichen Dai
- Cardiac and Osteochondral Tissue Engineering (COTE) Group, School of Medicine, The Chinese University of Hong Kong, Shenzhen 518172, China
| | - Pengchong Du
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Fengyi Yu
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Zhaowei Sun
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Jinying Zhang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
| | - Ke Cheng
- Department of Biomedical Engineering, Columbia University, New York, New York 10027, United States
| | - Junnan Tang
- Department of Cardiology, the First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, China
- Key Laboratory of Cardiac Injury and Repair of Henan Province, Zhengzhou, Henan 450052, China
- Henan Province Clinical Research Center for Cardiovascular Diseases, Zhengzhou, Henan 450052, China
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2
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Yahyazadeh R, Baradaran Rahimi V, Askari VR. Stem cell and exosome therapies for regenerating damaged myocardium in heart failure. Life Sci 2024; 351:122858. [PMID: 38909681 DOI: 10.1016/j.lfs.2024.122858] [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: 05/09/2024] [Revised: 06/13/2024] [Accepted: 06/18/2024] [Indexed: 06/25/2024]
Abstract
Finding novel treatments for cardiovascular diseases (CVDs) is a hot topic in medicine; cell-based therapies have reported promising news for controlling dangerous complications of heart disease such as myocardial infarction (MI) and heart failure (HF). Various progenitor/stem cells were tested in various in-vivo, in-vitro, and clinical studies for regeneration or repairing the injured tissue in the myocardial to accelerate the healing. Fetal, adult, embryonic, and induced pluripotent stem cells (iPSC) have revealed the proper potency for cardiac tissue repair. As an essential communicator among cells, exosomes with specific contacts (proteins, lncRNAs, and miRNAs) greatly promote cardiac rehabilitation. Interestingly, stem cell-derived exosomes have more efficiency than stem cell transplantation. Therefore, stem cells induced pluripotent stem cells (iPSCs), embryonic stem cells (ESCs), cardiac stem cells (CDC), and skeletal myoblasts) and their-derived exosomes will probably be considered an alternative therapy for CVDs remedy. In addition, stem cell-derived exosomes have been used in the diagnosis/prognosis of heart diseases. In this review, we explained the advances of stem cells/exosome-based treatment, their beneficial effects, and underlying mechanisms, which will present new insights in the clinical field in the future.
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Affiliation(s)
- Roghayeh Yahyazadeh
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Vafa Baradaran Rahimi
- Department of Cardiovascular Diseases, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Vahid Reza Askari
- Pharmacological Research Center of Medicinal Plants, Mashhad University of Medical Sciences, Mashhad, Iran.
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3
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Carvalho AB, Kasai-Brunswick TH, Campos de Carvalho AC. Advanced cell and gene therapies in cardiology. EBioMedicine 2024; 103:105125. [PMID: 38640834 PMCID: PMC11052923 DOI: 10.1016/j.ebiom.2024.105125] [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: 10/31/2023] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/21/2024] Open
Abstract
We review the evidence for the presence of stem/progenitor cells in the heart and the preclinical and clinical data using diverse cell types for the therapy of cardiac diseases. We highlight the failure of adult stem/progenitor cells to ameliorate heart function in most cardiac diseases, with the possible exception of refractory angina. The use of pluripotent stem cell-derived cardiomyocytes is analysed as a viable alternative therapeutic option but still needs further research at preclinical and clinical stages. We also discuss the use of direct reprogramming of cardiac fibroblasts into cardiomyocytes and the use of extracellular vesicles as therapeutic agents in ischemic and non-ischemic cardiac diseases. Finally, gene therapies and genome editing for the treatment of hereditary cardiac diseases, ablation of genes responsible for atherosclerotic disease, or modulation of gene expression in the heart are discussed.
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Affiliation(s)
- Adriana Bastos Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Tais Hanae Kasai-Brunswick
- Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Centro Nacional de Biologia Estrutural e Bioimagem (CENABIO), Universidade Federal do Rio de Janeiro, Rio de Janeiro, RJ, Brazil; Instituto Nacional de Ciência e Tecnologia em Medicina Regenerativa, Universidade Federal do RIo de Janeiro, Rio de Janeiro, RJ, Brazil.
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4
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Li H, Tang Q, Yang T, Wang Z, Li D, Wang L, Li L, Chen Y, Huang H, Zhang Y, Chen Y. Segregation of morphogenetic regulatory function of Shox2 from its cell fate guardian role in sinoatrial node development. Commun Biol 2024; 7:385. [PMID: 38553636 PMCID: PMC10980793 DOI: 10.1038/s42003-024-06039-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2023] [Accepted: 03/11/2024] [Indexed: 04/02/2024] Open
Abstract
Shox2 plays a vital role in the morphogenesis and physiological function of the sinoatrial node (SAN), the primary cardiac pacemaker, manifested by the formation of a hypoplastic SAN and failed differentiation of pacemaker cells in Shox2 mutants. Shox2 and Nkx2-5 are co-expressed in the developing SAN and regulate the fate of the pacemaker cells through a Shox2-Nkx2-5 antagonistic mechanism. Here we show that simultaneous inactivation of Nkx2-5 in the SAN of Shox2 mutants (dKO) rescued the pacemaking cell fate but not the hypoplastic defects, indicating uncoupling of SAN cell fate determination and morphogenesis. Single-cell RNA-seq revealed that the presumptive SAN cells of Shox2-/- mutants failed to activate pacemaking program but remained in a progenitor state preceding working myocardium, while both wildtype and dKO SAN cells displayed normal pacemaking cell fate with similar cellular state. Shox2 thus acts as a safeguard but not a determinant to ensure the pacemaking cell fate through the Shox2-Nkx2-5 antagonistic mechanism, which is segregated from its morphogenetic regulatory function in SAN development.
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Affiliation(s)
- Hua Li
- Key Laboratory of Stem Cell Engineering and Regenerative Medicine of Fujian Province University, Fujian Medical University, Fuzhou, Fujian Province, 350122, PR China.
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA.
- Southern Center for Biomedical Research and Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, 350108, PR China.
| | - Qinghuang Tang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
- Department of Oral Biology, School of Dental Medicine, University at Buffalo, Buffalo, NY, 14214, USA
| | - Tianfang Yang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
| | - Zhengsen Wang
- Southern Center for Biomedical Research and Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, 350108, PR China
| | - Dainan Li
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
| | - Linyan Wang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
- Department of Stomatology, Chengdu Second People's Hospital, Chengdu, Sichuan Province, 610021, PR China
| | - Liwen Li
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
- Department of Biological Sciences, College of Arts and Sciences, University at Buffalo, Buffalo, NY, 14260, USA
| | - Yaoyi Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
| | - Hai Huang
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA
| | - Yanding Zhang
- Southern Center for Biomedical Research and Fujian Key Laboratory of Developmental and Neural Biology, College of Life Sciences, Fujian Normal University, Fuzhou, Fujian Province, 350108, PR China
| | - YiPing Chen
- Department of Cell and Molecular Biology, Tulane University, New Orleans, LA, 70118, USA.
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5
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Zaib S, Areeba, Khan I. Purinergic Signaling and its Role in the Stem Cell Differentiation. Mini Rev Med Chem 2024; 24:863-883. [PMID: 37828668 DOI: 10.2174/0113895575261206231003151416] [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: 05/07/2023] [Revised: 07/30/2023] [Accepted: 08/30/2023] [Indexed: 10/14/2023]
Abstract
Purinergic signaling is a mechanism in which extracellular purines and pyrimidines interact with specialized cell surface receptors known as purinergic receptors. These receptors are divided into two families of P1 and P2 receptors, each responding to different nucleosides and nucleotides. P1 receptors are activated by adenosine, while P2 receptors are activated by pyrimidine and purines. P2X receptors are ligand-gated ion channels, including seven subunits (P2X1-7). However, P2Y receptors are the G-protein coupled receptors comprising eight subtypes (P2Y1/2/4/6/11/12/13/14). The disorder in purinergic signaling leads to various health-related issues and diseases. In various aspects, it influences the activity of non-neuronal cells and neurons. The molecular mechanism of purinergic signaling provides insight into treating various human diseases. On the contrary, stem cells have been investigated for therapeutic applications. Purinergic signaling has shown promising effect in stem cell engraftment. The immune system promotes the autocrine and paracrine mechanisms and releases the significant factors essential for successful stem cell therapy. Each subtype of purinergic receptor exerts a beneficial effect on the damaged tissue. The most common effect caused by purinergic signaling is the proliferation and differentiation that treat different health-related conditions.
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Affiliation(s)
- Sumera Zaib
- Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore, 54590, Pakistan
| | - Areeba
- Department of Basic and Applied Chemistry, Faculty of Science and Technology, University of Central Punjab, Lahore, 54590, Pakistan
| | - Imtiaz Khan
- Manchester Institute of Biotechnology, The University of Manchester, 131 Princess Street, Manchester, M1 7DN, United Kingdom
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Deszcz I. Stem Cell-Based Therapy and Cell-Free Therapy as an Alternative Approach for Cardiac Regeneration. Stem Cells Int 2023; 2023:2729377. [PMID: 37954462 PMCID: PMC10635745 DOI: 10.1155/2023/2729377] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 06/21/2023] [Accepted: 10/10/2023] [Indexed: 11/14/2023] Open
Abstract
The World Health Organization reports that cardiovascular diseases (CVDs) represent 32% of all global deaths. The ineffectiveness of conventional therapies in CVDs encourages the development of novel, minimally invasive therapeutic strategies for the healing and regeneration of damaged tissue. The self-renewal capacity, multilineage differentiation, lack of immunogenicity, and immunosuppressive properties of mesenchymal stem cells (MSCs) make them a promising option for CVDs. However, growing evidence suggests that myocardial regeneration occurs through paracrine factors and extracellular vesicle (EV) secretion, rather than through differentiation into cardiomyocytes. Research shows that stem cells secrete or surface-shed into their culture media various cytokines, chemokines, growth factors, anti-inflammatory factors, and EVs, which constitute an MSC-conditioned medium (MSC-CM) or the secretome. The use of MSC-CM enhances cardiac repair through resident heart cell differentiation, proliferation, scar mass reduction, a decrease in infarct wall thickness, and cardiac function improvement comparable to MSCs without their side effects. This review highlights the limitations and benefits of therapies based on stem cells and their secretome as an innovative treatment of CVDs.
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Affiliation(s)
- Iwona Deszcz
- Department of Immunopathology and Molecular Biology, Wroclaw Medical University, Borowska 211, 50-556, Wroclaw, Poland
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Chatchavalvanich S, Boomsma RA, Tietema JM, Geenen DL. Inhibition of Gap Junction Formation Prior to Implantation of Bone Marrow-Derived Mesenchymal Cells Improves Function in the Ischemic Myocardium. Int J Mol Sci 2023; 24:9653. [PMID: 37298612 PMCID: PMC10253678 DOI: 10.3390/ijms24119653] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2023] [Revised: 05/22/2023] [Accepted: 05/25/2023] [Indexed: 06/12/2023] Open
Abstract
Bone marrow-derived mesenchymal stem cells (BM-MSC) are reported to induce beneficial effects in the heart following ischemia, but a loss of these cells within hours of implantation could significantly diminish their long-term effect. We hypothesized that early coupling between BM-MSC and ischemic cardiomyocytes through gap junctions (GJ) may play an important role in stem cell survival and retention in the acute phase of myocardial ischemia. To determine the effect of GJ inhibition on murine BM-MSC in vivo, we induced ischemia in mice using 90 min left anterior descending coronary artery (LAD) occlusion followed by BM-MSC implantation and reperfusion. The inhibition of GJ coupling prior to BM-MSC implantation led to early improvement in cardiac function compared to mice in which GJ coupling was not inhibited. Our results with in vitro studies also demonstrated increased survival in BM-MSCs subjected to hypoxia after inhibition of GJ. While functional GJ are critical for the long-term integration of stem cells within the myocardium, early GJ communication may represent a novel paradigm whereby ischemic cardiomyocytes induce a "bystander effect" when coupled to newly transplanted BM-MSC and thus impair cell retention and survival.
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Affiliation(s)
- Santipongse Chatchavalvanich
- Department of Basic Biomedical Sciences, Dr. William M. Scholl College of Podiatric Medicine, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA;
| | - Robert A. Boomsma
- Biology Department, Trinity Christian College, Palos Heights, IL 60463, USA;
| | - Jack M. Tietema
- Michigan State University College of Human Medicine, Grand Rapids, MI 49503, USA;
| | - David L. Geenen
- Physician Assistant Studies Department, College of Health Professions, Grand Valley State University, Grand Rapids, MI 49503, USA
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8
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Mendoza A, Karch J. Keeping the beat against time: Mitochondrial fitness in the aging heart. FRONTIERS IN AGING 2022; 3:951417. [PMID: 35958271 PMCID: PMC9360554 DOI: 10.3389/fragi.2022.951417] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2022] [Accepted: 06/30/2022] [Indexed: 11/21/2022]
Abstract
The process of aging strongly correlates with maladaptive architectural, mechanical, and biochemical alterations that contribute to the decline in cardiac function. Consequently, aging is a major risk factor for the development of heart disease, the leading cause of death in the developed world. In this review, we will summarize the classic and recently uncovered pathological changes within the aged heart with an emphasis on the mitochondria. Specifically, we describe the metabolic changes that occur in the aging heart as well as the loss of mitochondrial fitness and function and how these factors contribute to the decline in cardiomyocyte number. In addition, we highlight recent pharmacological, genetic, or behavioral therapeutic intervention advancements that may alleviate age-related cardiac decline.
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Affiliation(s)
- Arielys Mendoza
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, United States
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States
| | - Jason Karch
- Department of Integrative Physiology, Baylor College of Medicine, Houston, TX, United States
- Cardiovascular Research Institute, Baylor College of Medicine, Houston, TX, United States
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9
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Latar NM, Mahkamova K, Elson J, Karnik I, Sutherland R, Aspinall S, Meeson A. Impact of transforming growth factor beta 1 on normal and thyroid cancer side population cells. Endocrine 2022; 76:359-368. [PMID: 35118633 PMCID: PMC9068642 DOI: 10.1007/s12020-022-02990-4] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/14/2021] [Accepted: 01/19/2022] [Indexed: 12/22/2022]
Abstract
PURPOSE To determine the impact of exogenous transforming growth factor beta 1 (TGF-β1) on side population (SP) cells isolated from normal, papillary thyroid cancer and anaplastic thyroid cancer cell lines and from human thyroid tissues. METHODS All cell populations were stained with Hoechst 33342 and analysed using dual wavelength flow cytometry to identify SP cells. This SP assay was used to assess the impact of TGF-β1 treatment and withdrawal of treatment on SP percentages. Semi-quantitative and quantitative PCR were used for molecular analysis of cells pre and post TGF-β1 treatment. RESULTS All cell lines expressed mRNA for both TGFB1 and its receptors, as well as showing variable expression of CDH1 and CDH2, with expressing of CDH1 being highest and CDH2 being lowest in the normal cell line. Exposure to exogenous TGF-β1 resulted in a reduction in mRNA expression of ABCG2 compared to controls which was significant between control and treated cancer cell lines. SP cells were isolated from primary human thyroid tissues, with numbers being significantly higher in papillary thyroid cancers. Exposure to TGF-β1 decreased the SP percentage in both thyroid cancer cell lines and completely abrogated these cells in the primary papillary thyroid cancer cultures. On withdrawal of TGF-β1 the SP phenotype was restored in the cancer cell lines and SP percentages increased to above that of untreated cells. CONCLUSIONS TGF-β1 exposure transiently regulates thyroid cancer SP cells, leading to a reduction in SP percentages, while withdrawal of TGF-β1 results in restoration of the SP phenotype.
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Affiliation(s)
- Nani Md Latar
- Department of Surgery, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
- Newcastle University Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
| | - Kamilla Mahkamova
- Newcastle University Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
| | - Joanna Elson
- Newcastle University Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
| | - Isha Karnik
- Newcastle University Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
| | - Rachel Sutherland
- Newcastle University Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK
| | - Sebastian Aspinall
- Department of General Surgery, Aberdeen Royal Infirmary, Foresterhill, Aberdeen, AB252ZN, UK
| | - Annette Meeson
- Newcastle University Bioscience Institute, Newcastle University, International Centre for Life, Central Parkway, Newcastle upon Tyne, NE1 3BZ, UK.
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Anto Michel N, Ljubojevic-Holzer S, Bugger H, Zirlik A. Cellular Heterogeneity of the Heart. Front Cardiovasc Med 2022; 9:868466. [PMID: 35548426 PMCID: PMC9081371 DOI: 10.3389/fcvm.2022.868466] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Accepted: 03/23/2022] [Indexed: 11/18/2022] Open
Abstract
Recent advances in technology such as the introduction of high throughput multidimensional tools like single cell sequencing help to characterize the cellular composition of the human heart. The diversity of cell types that has been uncovered by such approaches is by far greater than ever expected before. Accurate identification of the cellular variety and dynamics will not only facilitate a much deeper understanding of cardiac physiology but also provide important insights into mechanisms underlying its pathological transformation. Distinct cellular patterns of cardiac cell clusters may allow differentiation between a healthy heart and a sick heart while potentially predicting future disease at much earlier stages than currently possible. These advances have already extensively improved and will ultimately revolutionize our knowledge of the mechanisms underlying cardiovascular disease as such. In this review, we will provide an overview of the cells present in the human and rodent heart as well as genes that may be used for their identification.
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11
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Kukal S, Guin D, Rawat C, Bora S, Mishra MK, Sharma P, Paul PR, Kanojia N, Grewal GK, Kukreti S, Saso L, Kukreti R. Multidrug efflux transporter ABCG2: expression and regulation. Cell Mol Life Sci 2021; 78:6887-6939. [PMID: 34586444 PMCID: PMC11072723 DOI: 10.1007/s00018-021-03901-y] [Citation(s) in RCA: 60] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 06/24/2021] [Accepted: 07/15/2021] [Indexed: 12/15/2022]
Abstract
The adenosine triphosphate (ATP)-binding cassette efflux transporter G2 (ABCG2) was originally discovered in a multidrug-resistant breast cancer cell line. Studies in the past have expanded the understanding of its role in physiology, disease pathology and drug resistance. With a widely distributed expression across different cell types, ABCG2 plays a central role in ATP-dependent efflux of a vast range of endogenous and exogenous molecules, thereby maintaining cellular homeostasis and providing tissue protection against xenobiotic insults. However, ABCG2 expression is subjected to alterations under various pathophysiological conditions such as inflammation, infection, tissue injury, disease pathology and in response to xenobiotics and endobiotics. These changes may interfere with the bioavailability of therapeutic substrate drugs conferring drug resistance and in certain cases worsen the pathophysiological state aggravating its severity. Considering the crucial role of ABCG2 in normal physiology, therapeutic interventions directly targeting the transporter function may produce serious side effects. Therefore, modulation of transporter regulation instead of inhibiting the transporter itself will allow subtle changes in ABCG2 activity. This requires a thorough comprehension of diverse factors and complex signaling pathways (Kinases, Wnt/β-catenin, Sonic hedgehog) operating at multiple regulatory levels dictating ABCG2 expression and activity. This review features a background on the physiological role of transporter, factors that modulate ABCG2 levels and highlights various signaling pathways, molecular mechanisms and genetic polymorphisms in ABCG2 regulation. This understanding will aid in identifying potential molecular targets for therapeutic interventions to overcome ABCG2-mediated multidrug resistance (MDR) and to manage ABCG2-related pathophysiology.
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Affiliation(s)
- Samiksha Kukal
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Debleena Guin
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Chitra Rawat
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Shivangi Bora
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Manish Kumar Mishra
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Department of Biotechnology, Delhi Technological University, Shahbad Daulatpur, Main Bawana Road, Delhi, 110042, India
| | - Priya Sharma
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
| | - Priyanka Rani Paul
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Neha Kanojia
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India
| | - Gurpreet Kaur Grewal
- Department of Biotechnology, Kanya Maha Vidyalaya, Jalandhar, Punjab, 144004, India
| | - Shrikant Kukreti
- Nucleic Acids Research Lab, Department of Chemistry, University of Delhi (North Campus), Delhi, 110007, India
| | - Luciano Saso
- Department of Physiology and Pharmacology "Vittorio Erspamer", Sapienza University of Rome, P. le Aldo Moro 5, 00185, Rome, Italy
| | - Ritushree Kukreti
- Genomics and Molecular Medicine Unit, Institute of Genomics and Integrative Biology (IGIB), Council of Scientific and Industrial Research (CSIR), Mall Road, Delhi, 110007, India.
- Academy of Scientific and Innovative Research (AcSIR), Ghaziabad, 201002, India.
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12
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Yuko AE, Carvalho Rigaud VO, Kurian J, Lee JH, Kasatkin N, Behanan M, Wang T, Luchesse AM, Mohsin S, Koch WJ, Wang H, Khan M. LIN28a induced metabolic and redox regulation promotes cardiac cell survival in the heart after ischemic injury. Redox Biol 2021; 47:102162. [PMID: 34628272 PMCID: PMC8515487 DOI: 10.1016/j.redox.2021.102162] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2021] [Revised: 10/04/2021] [Accepted: 10/07/2021] [Indexed: 12/28/2022] Open
Abstract
RATIONALE Cell-based therapeutics have been extensively used for cardiac repair yet underperform due to inability of the donated cells to survive in near anoxia after cardiac injury. Cellular metabolism is linked to maintenance of cardiac stem cell (CSC) renewal, proliferation and survival. Ex vivo expansion alters (CSC) metabolism increasing reliance on oxygen dependent respiration. Whether promoting 'metabolic flexibility' in CSCs augments their ability to survive in near anoxia and repair the heart after injury remains untested. OBJECTIVE Determine the effect of LIN28a induced metabolic flexibility on cardiac tissue derived stem like cell (CTSC) survival and repair after cardiac injury. METHODS AND RESULTS LIN28a expression coincides during heart development but is lost in adult CTSCs. Reintroduction of LIN28a in adult CTSC (CTSC-LIN) increased proliferation, survival, expression of pluripotency genes and reduced senescence compared to control (CTSC-GFP). Metabolomic analysis show glycolytic intermediates upregulated in CTSC-LIN together with increased lactate production, pyruvate kinase activity, glucose uptake, ECAR and expression of glycolytic enzymes compared to CTSC-GFP. Additionally, CTSC-LIN showed significantly reduced ROS generation and increase antioxidant markers. In response to H2O2 induced oxidative stress, CTSC-LIN showed increased survival and expression of glycolytic genes. LIN28a salutary effects on CTSCs were linked to PDK1/let-7 signaling pathway with loss of PDK1 or alteration of let-7 abrogating LIN28a effects. Following transplantation in the heart after myocardial infarction (MI), CTSC-LIN showed 6% survival rate at day 7 after injection compared to control cells together with increased proliferation and significant increase in cardiac structure and function 8 weeks after MI. Finally, CSTC-LIN showed enhanced ability to secrete paracrine factors under hypoxic conditions and ability to promote cardiomyocyte proliferation following ischemic cardiac injury. CONCLUSIONS LIN28a modification promotes metabolic flexibility in CTSCs enhancing proliferation and survival post transplantation including ability to repair the heart after myocardial injury.
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Affiliation(s)
| | | | | | - Ji H Lee
- Center for Metabolic Disease Research (CMDR), USA
| | | | | | - Tao Wang
- Cardiovascular Research Institute (CVRC), USA
| | | | - Sadia Mohsin
- Cardiovascular Research Institute (CVRC), USA; Department of Pharmacology, LKSOM, Temple University, LKSOM, Temple University, USA
| | - Walter J Koch
- Center for Translational Medicine (CTM), LKSOM, Temple University, USA
| | - Hong Wang
- Center for Metabolic Disease Research (CMDR), USA
| | - Mohsin Khan
- Center for Metabolic Disease Research (CMDR), USA; Department of Physiology, LKSOM, Temple University, USA.
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13
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Kasai-Brunswick TH, Carvalho AB, Campos de Carvalho AC. Stem cell therapies in cardiac diseases: Current status and future possibilities. World J Stem Cells 2021; 13:1231-1247. [PMID: 34630860 PMCID: PMC8474720 DOI: 10.4252/wjsc.v13.i9.1231] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 07/26/2021] [Accepted: 08/10/2021] [Indexed: 02/06/2023] Open
Abstract
Cardiovascular diseases represent the world's leading cause of death. In this heterogeneous group of diseases, ischemic cardiomyopathies are the most devastating and prevalent, estimated to cause 17.9 million deaths per year. Despite all biomedical efforts, there are no effective treatments that can replace the myocytes lost during an ischemic event or progression of the disease to heart failure. In this context, cell therapy is an emerging therapeutic alternative to treat cardiovascular diseases by cell administration, aimed at cardiac regeneration and repair. In this review, we will cover more than 30 years of cell therapy in cardiology, presenting the main milestones and drawbacks in the field and signaling future challenges and perspectives. The outcomes of cardiac cell therapies are discussed in three distinct aspects: The search for remuscularization by replacement of lost cells by exogenous adult cells, the endogenous stem cell era, which pursued the isolation of a progenitor with the ability to induce heart repair, and the utilization of pluripotent stem cells as a rich and reliable source of cardiomyocytes. Acellular therapies using cell derivatives, such as microvesicles and exosomes, are presented as a promising cell-free therapeutic alternative.
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Affiliation(s)
- Tais Hanae Kasai-Brunswick
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Adriana Bastos Carvalho
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
| | - Antonio Carlos Campos de Carvalho
- National Center of Structural Biology and Bioimaging, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- National Institute of Science and Technology in Regenerative Medicine, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil
- Carlos Chagas Filho Institute of Biophysics, Federal University of Rio de Janeiro, Rio de Janeiro 21941-902, RJ, Brazil.
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14
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Fanni D, Gerosa C, Loddo C, Castagnola M, Fanos V, Zaffanello M, Faa G. Stem/progenitor cells in fetuses and newborns: overview of immunohistochemical markers. CELL REGENERATION (LONDON, ENGLAND) 2021; 10:22. [PMID: 34219203 PMCID: PMC8255250 DOI: 10.1186/s13619-021-00084-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/26/2020] [Accepted: 04/12/2021] [Indexed: 12/26/2022]
Abstract
Microanatomy of the vast majority of human organs at birth is characterized by marked differences as compared to adult organs, regarding their architecture and the cell types detectable at histology. In preterm neonates, these differences are even more evident, due to the lower level of organ maturation and to ongoing cell differentiation. One of the most remarkable finding in preterm tissues is the presence of huge amounts of stem/progenitor cells in multiple organs, including kidney, brain, heart, adrenals, and lungs. In other organs, such as liver, the completely different burden of cell types in preterm infants is mainly related to the different function of the liver during gestation, mainly focused on hematopoiesis, a function that is taken by bone marrow after birth. Our preliminary studies showed that the antigens expressed by stem/progenitors differ significantly from one organ to the next. Moreover, within each developing human tissue, reactivity for different stem cell markers also changes during gestation, according with the multiple differentiation steps encountered by each progenitor during development. A better knowledge of stem/progenitor cells of preterms will allow neonatologists to boost preterm organ maturation, favoring the differentiation of the multiple cells types that characterize each organ in at term neonates.
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Affiliation(s)
- D Fanni
- Division of Pathology, University Hospital San Giovanni Di Dio, via Ospedale, 54, Cagliari, Italy.,Department of Biology, College of Science and Technology, Temple University, Phidelphia, USA
| | - C Gerosa
- Division of Pathology, University Hospital San Giovanni Di Dio, via Ospedale, 54, Cagliari, Italy.,Department of Biology, College of Science and Technology, Temple University, Phidelphia, USA
| | - C Loddo
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - M Castagnola
- Laboratory of Biochemistry and Metabolomics, IRCCS Fondazione Santa Lucia, Rome, Italy
| | - V Fanos
- Neonatal Intensive Care Unit, Department of Surgical Sciences, University of Cagliari, Cagliari, Italy
| | - M Zaffanello
- Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, University of Verona, Piazzale Stefani, 1, I-37126, Verona, Italy.
| | - G Faa
- Division of Pathology, University Hospital San Giovanni Di Dio, via Ospedale, 54, Cagliari, Italy.,Department of Biology, College of Science and Technology, Temple University, Phidelphia, USA
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15
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Beliën H, Evens L, Hendrikx M, Bito V, Bronckaers A. Combining stem cells in myocardial infarction: The road to superior repair? Med Res Rev 2021; 42:343-373. [PMID: 34114238 DOI: 10.1002/med.21839] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2021] [Revised: 05/04/2021] [Accepted: 05/29/2021] [Indexed: 12/25/2022]
Abstract
Myocardial infarction irreversibly destroys millions of cardiomyocytes in the ventricle, making it the leading cause of heart failure worldwide. Over the past two decades, many progenitor and stem cell types were proposed as the ideal candidate to regenerate the heart after injury. The potential of stem cell therapy has been investigated thoroughly in animal and human studies, aiming at cardiac repair by true tissue replacement, by immune modulation, or by the secretion of paracrine factors that stimulate endogenous repair processes. Despite some successful results in animal models, the outcome from clinical trials remains overall disappointing, largely due to the limited stem cell survival and retention after transplantation. Extensive interest was developed regarding the combinational use of stem cells and various priming strategies to improve the efficacy of regenerative cell therapy. In this review, we provide a critical discussion of the different stem cell types investigated in preclinical and clinical studies in the field of cardiac repair. Moreover, we give an update on the potential of stem cell combinations as well as preconditioning and explore the future promises of these novel regenerative strategies.
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Affiliation(s)
- Hanne Beliën
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Lize Evens
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Marc Hendrikx
- Faculty of Medicine and Life Sciences, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Virginie Bito
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
| | - Annelies Bronckaers
- Biomedical Research Institute (BIOMED), Department of Cardio and Organ Systems, UHasselt-Hasselt University, Agoralaan, Diepenbeek, Belgium
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16
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Lauschke K, Volpini L, Liu Y, Vinggaard AM, Hall VJ. A Comparative Assessment of Marker Expression Between Cardiomyocyte Differentiation of Human Induced Pluripotent Stem Cells and the Developing Pig Heart. Stem Cells Dev 2021; 30:374-385. [PMID: 33599158 DOI: 10.1089/scd.2020.0184] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
The course of differentiation of pluripotent stem cells into cardiomyocytes and the intermediate cell types are characterized using molecular markers for different stages of development. These markers have been selected primarily from studies in the mouse and from a limited number of human studies. However, it is not clear how well mouse cardiogenesis compares with human cardiogenesis at the molecular level. We tackle this issue by analyzing and comparing the expression of common cardiomyogenesis markers [platelet-derived growth factor receptor, alpha polypeptide (PDGFR-α), fetal liver kinase 1 (FLK1), ISL1, NK2 homeobox 5 (NKX2.5), cardiac troponin T (CTNT), connexin43 (CX43), and myosin heavy chain 7 (MYHC-B)] in the developing pig heart at embryonic day (E)15, E16, E18, E20, E22, and E24 and in differentiating cardiomyocytes from human induced pluripotent stem cells (hiPSCs). We found that porcine expression of the mesoderm marker FLK1 and the cardiac progenitor marker ISL1 was in line with our differentiating hiPSC and reported murine expression. The cardiac lineage marker NKX2.5 was expressed at almost all stages in the pig and hiPSC, with an earlier onset in the hiPSC compared with reported murine expression. Markers of immature cardiomyocytes, CTNT, and MYHC-B were consistently expressed throughout E16-E70 in the pig, which is comparable with mouse development, whereas the markers increased over time in the hiPSC. However, the commonly used mature cardiomyocyte marker, CX43, should be used with caution, as it was also expressed in the pig mesoderm, as well as hiPSC immature cardiomyocytes, while this has not been reported in mice. Based on our observations in the various species, we suggest to use FLK1/PDGFR-α for identifying cardiac mesoderm and ISL1/NKX2.5 for cardiac progenitors. Furthermore, a combination of two or more of the following, CTNT+/MYHC-B+/ISL1+ could mark immature cardiomyocytes and CTNT+/ISL1- mature cardiomyocytes. CX43 should be used together with sarcomeric proteins. This knowledge may help improving differentiation of hiPSC into more in vivo-like cardiac tissue in the future.
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Affiliation(s)
- Karin Lauschke
- National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark.,Department for Biotechnology and Biomedicine, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Luca Volpini
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Yong Liu
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
| | - Anne Marie Vinggaard
- National Food Institute, Technical University of Denmark, Kongens Lyngby, Denmark
| | - Vanessa Jane Hall
- Department of Veterinary and Animal Sciences, University of Copenhagen, Frederiksberg, Denmark
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17
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Sarkar A, Saha S, Paul A, Maji A, Roy P, Maity TK. Understanding stem cells and its pivotal role in regenerative medicine. Life Sci 2021; 273:119270. [PMID: 33640402 DOI: 10.1016/j.lfs.2021.119270] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Revised: 02/06/2021] [Accepted: 02/14/2021] [Indexed: 02/07/2023]
Abstract
Stem cells (SCs) are clonogenic cells that develop into the specialized cells which later responsible for making up various types of tissue in the human body. SCs are not only the appropriate source of information for cell division, molecular and cellular processes, and tissue homeostasis but also one of the major putative biological aids to diagnose and cure various degenerative diseases. This study emphasises on various research outputs that occurred in the past two decades. This will give brief information on classification, differentiation, detection, and various isolation techniques of SCs. Here, the various signalling pathways which includes WNT, Sonic hedgehog, Notch, BMI1 and C-met pathways and how does it effect on the regeneration of various classes of SCs and factors that regulates the potency of the SCs are also been discussed. We also focused on the application of SCs in the area of regenerative medicine along with the cellular markers that are useful as salient diagnostic or curative tools or in both, by the process of reprogramming, which includes diabetes, cancer, cardiovascular disorders and neurological disorders. The biomarkers that are mentioned in various literatures and experiments include PDX1, FOXA2, HNF6, and NKX6-1 (for diabetes); CD33, CD24, CD133 (for cancer); c-Kit, SCA-1, Wilm's tumor 1 (for cardiovascular disorders); and OCT4, SOX2, c-MYC, EN1, DAT and VMAT2 (for neurological disorders). In this review, we come to know the advancements and scopes of potential SC-based therapies, its diverse applications in clinical fields that can be helpful in the near future.
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Affiliation(s)
- Arnab Sarkar
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Sanjukta Saha
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Abhik Paul
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Avik Maji
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Puspita Roy
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India
| | - Tapan Kumar Maity
- Department of Pharmaceutical Technology, Jadavpur University, West Bengal, Kolkata 700032, India.
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18
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Evolution of Stem Cells in Cardio-Regenerative Therapy. Stem Cells 2021. [DOI: 10.1007/978-3-030-77052-5_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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19
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Li X, Ou X, Luo G, Ou X, Xie Y, Ying M, Qu W, Zuo H, Qi X, Wang Y, Liu Z, Zhu L. Mdr1a, Bcrp and Mrp2 regulate the efficacy and toxicity of mesaconitine and hypaconitine by altering their tissue accumulation and in vivo residence. Toxicol Appl Pharmacol 2020; 409:115332. [PMID: 33171190 DOI: 10.1016/j.taap.2020.115332] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2020] [Revised: 11/01/2020] [Accepted: 11/05/2020] [Indexed: 02/05/2023]
Abstract
Mesaconitine (MA) and hypaconitine (HA) are the main bioactive/toxic alkaloids of Aconitum carmichaelii Debx, and MDR1, BCRP and MRP2 are involved in their efflux in vitro. This study aimed to explore the effects of Mdr1a, Bcrp and Mrp2 on the efficacy/toxicity of MA and HA by using efflux transporter gene knockout mouse models. The analgesic and anti-inflammatory effects, neurotoxicity/cardiotoxicity, and pharmacokinetic profiles of MA and HA were studied. Compared to wild-type mice, the analgesic effects of MA or HA were significantly enhanced in Mdr1a--/-, Bcrp1-/- and Mrp2-/- mice, and the anti-inflammatory effects notably increased in Bcrp1-/- and Mrp2-/- mice. Compared to wild-type mice, Mdr1a-/-, Bcrp1-/- and Mrp2-/- mice suffered from severe karyopyknosis and edema in the brain after MA or HA treatment. Meanwhile, significant arrhythmia appeared, and the heart rate and RR-interval were greatly altered in Mdr1a-/-, Bcrp1-/- and Mrp2-/- mice. Additionally, obvious disorder of cardiomyocytes were observed, and the CK and cTnT (indicators of heart injury) levels were greatly enhanced in efflux transporter gene knockout mice. The brain levels of MA and HA were markedly increased in Mdr1a-/-, Bcrp1-/- and Mrp2-/- mice, and the heart levels of MA and HA enhanced greatly in Mdr1a-/- mice. The MRT0-t values of MA and HA were remarkably enhanced in most efflux transporter gene knockout mice. In conclusion, Mdr1a, Bcrp and Mrp2 were all involved in regulating the efficacy/toxicity of MA and HA by altering their tissue accumulation and in vivo residence. Among the three efflux transporters, Mdr1a had a superior regulatory effect.
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Affiliation(s)
- Xiaocui Li
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Xiaowen Ou
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Guangkuo Luo
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Xiaojun Ou
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Yushan Xie
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Mengdi Ying
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Wei Qu
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Huilin Zuo
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Xiaoxiao Qi
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Ying Wang
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China
| | - Zhongqiu Liu
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China.
| | - Lijun Zhu
- International Institute for Translational Chinese Medicine, School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, Guangzhou, Guangdong Province 510006, PR China.
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20
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Zhang X, Powell K, Li L. Breast Cancer Stem Cells: Biomarkers, Identification and Isolation Methods, Regulating Mechanisms, Cellular Origin, and Beyond. Cancers (Basel) 2020; 12:E3765. [PMID: 33327542 PMCID: PMC7765014 DOI: 10.3390/cancers12123765] [Citation(s) in RCA: 79] [Impact Index Per Article: 15.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/03/2020] [Accepted: 12/10/2020] [Indexed: 02/07/2023] Open
Abstract
Despite recent advances in diagnosis and treatment, breast cancer (BC) is still a major cause of cancer-related mortality in women. Breast cancer stem cells (BCSCs) are a small but significant subpopulation of heterogeneous breast cancer cells demonstrating strong self-renewal and proliferation properties. Accumulating evidence has proved that BCSCs are the driving force behind BC tumor initiation, progression, metastasis, drug resistance, and recurrence. As a heterogeneous disease, BC contains a full spectrum of different BC subtypes, and different subtypes of BC further exhibit distinct subtypes and proportions of BCSCs, which correspond to different treatment responses and disease-specific outcomes. This review summarized the current knowledge of BCSC biomarkers and their clinical relevance, the methods for the identification and isolation of BCSCs, and the mechanisms regulating BCSCs. We also discussed the cellular origin of BCSCs and the current advances in single-cell lineage tracing and transcriptomics and their potential in identifying the origin and lineage development of BCSCs.
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Affiliation(s)
- Xiaoli Zhang
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH 43210, USA;
| | | | - Lang Li
- Department of Biomedical Informatics, College of Medicine, The Ohio State University, 320B Lincoln Tower, 1800 Cannon Dr., Columbus, OH 43210, USA;
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21
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Kurian J, Yuko AE, Kasatkin N, Rigaud VOC, Busch K, Harlamova D, Wagner M, Recchia FA, Wang H, Mohsin S, Houser SR, Khan M. Uncoupling protein 2-mediated metabolic adaptations define cardiac cell function in the heart during transition from young to old age. Stem Cells Transl Med 2020; 10:144-156. [PMID: 32964621 PMCID: PMC7780806 DOI: 10.1002/sctm.20-0123] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2020] [Revised: 07/20/2020] [Accepted: 08/17/2020] [Indexed: 12/13/2022] Open
Abstract
Cellular replacement in the heart is restricted to postnatal stages with the adult heart largely postmitotic. Studies show that loss of regenerative properties in cardiac cells seems to coincide with alterations in metabolism during postnatal development and maturation. Nevertheless, whether changes in cellular metabolism are linked to functional alternations in cardiac cells is not well studied. We report here a novel role for uncoupling protein 2 (UCP2) in regulation of functional properties in cardiac tissue derived stem‐like cells (CTSCs). CTSC were isolated from C57BL/6 mice aged 2 days (nCTSC), 2 month (CTSC), and 2 years old (aCTSC), subjected to bulk‐RNA sequencing that identifies unique transcriptome significantly different between CTSC populations from young and old heart. Moreover, results show that UCP2 is highly expressed in CTSCs from the neonatal heart and is linked to maintenance of glycolysis, proliferation, and survival. With age, UCP2 is reduced shifting energy metabolism to oxidative phosphorylation inversely affecting cellular proliferation and survival in aged CTSCs. Loss of UCP2 in neonatal CTSCs reduces extracellular acidification rate and glycolysis together with reduced cellular proliferation and survival. Mechanistically, UCP2 silencing is linked to significant alteration of mitochondrial genes together with cell cycle and survival signaling pathways as identified by RNA‐sequencing and STRING bioinformatic analysis. Hence, our study shows UCP2‐mediated metabolic profile regulates functional properties of cardiac cells during transition from neonatal to aging cardiac states.
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Affiliation(s)
- Justin Kurian
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Antonia E Yuko
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Nicole Kasatkin
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Vagner O C Rigaud
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Kelsey Busch
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Daria Harlamova
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Marcus Wagner
- Cardiovascular Research Institute (CVRC), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Fabio A Recchia
- Cardiovascular Research Institute (CVRC), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.,Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy.,Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Hong Wang
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Sadia Mohsin
- Cardiovascular Research Institute (CVRC), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Steven R Houser
- Cardiovascular Research Institute (CVRC), Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.,Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
| | - Mohsin Khan
- Center for Metabolic Disease Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA.,Department of Physiology, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania, USA
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22
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He L, Nguyen NB, Ardehali R, Zhou B. Heart Regeneration by Endogenous Stem Cells and Cardiomyocyte Proliferation: Controversy, Fallacy, and Progress. Circulation 2020; 142:275-291. [PMID: 32687441 DOI: 10.1161/circulationaha.119.045566] [Citation(s) in RCA: 92] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/25/2022]
Abstract
Ischemic heart disease is the leading cause of death worldwide. Myocardial infarction results in an irreversible loss of cardiomyocytes with subsequent adverse remodeling and heart failure. Identifying new sources for cardiomyocytes and promoting their formation represents a goal of cardiac biology and regenerative medicine. Within the past decade, many types of putative cardiac stem cells (CSCs) have been reported to regenerate the injured myocardium by differentiating into new cardiomyocytes. Some of these CSCs have been translated from bench to bed with reported therapeutic effectiveness. However, recent basic research studies on stem cell tracing have begun to question their fundamental biology and mechanisms of action, raising serious concerns over the myogenic potential of CSCs. We review the history of different types of CSCs within the past decade and provide an update of recent cell tracing studies that have challenged the origin and existence of CSCs. In addition to the potential role of CSCs in heart regeneration, proliferation of preexisting cardiomyocytes has recently gained more attention. This review will also evaluate the methodologic and technical aspects of past and current studies on CSCs and cardiomyocyte proliferation, with emphasis on technical strengths, advantages, and potential limitations of research approaches. While our understanding of cardiomyocyte generation and regeneration continues to evolve, it is important to address the shortcomings and inaccuracies in this field. This is best achieved by embracing technological advancements and improved methods to label single cardiomyocytes/progenitors and accurately investigate their developmental potential and fate/lineage commitment.
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Affiliation(s)
- Lingjuan He
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.)
| | - Ngoc B Nguyen
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Reza Ardehali
- Division of Cardiology, Department of Internal Medicine, David Geffen School of Medicine (N.B.N., R.A.), University of California, Los Angeles.,Eli and Edythe Broad Center of Regenerative Medicine and Stem Cell Research (N.B.N., R.A.), University of California, Los Angeles
| | - Bin Zhou
- State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China (L.H., B.Z.).,School of Life Science and Technology, ShanghaiTech University, Shanghai, China (B.Z.).,School of Life Science, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou, China (B.Z.).,Key Laboratory of Regenerative Medicine of Ministry of Education, Jinan University, Guangzhou, China (B.Z.)
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23
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Cianflone E, Torella M, Biamonte F, De Angelis A, Urbanek K, Costanzo FS, Rota M, Ellison-Hughes GM, Torella D. Targeting Cardiac Stem Cell Senescence to Treat Cardiac Aging and Disease. Cells 2020; 9:E1558. [PMID: 32604861 PMCID: PMC7349658 DOI: 10.3390/cells9061558] [Citation(s) in RCA: 80] [Impact Index Per Article: 16.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/19/2020] [Accepted: 06/25/2020] [Indexed: 12/13/2022] Open
Abstract
Adult stem/progenitor are a small population of cells that reside in tissue-specific niches and possess the potential to differentiate in all cell types of the organ in which they operate. Adult stem cells are implicated with the homeostasis, regeneration, and aging of all tissues. Tissue-specific adult stem cell senescence has emerged as an attractive theory for the decline in mammalian tissue and organ function during aging. Cardiac aging, in particular, manifests as functional tissue degeneration that leads to heart failure. Adult cardiac stem/progenitor cell (CSC) senescence has been accordingly associated with physiological and pathological processes encompassing both non-age and age-related decline in cardiac tissue repair and organ dysfunction and disease. Senescence is a highly active and dynamic cell process with a first classical hallmark represented by its replicative limit, which is the establishment of a stable growth arrest over time that is mainly secondary to DNA damage and reactive oxygen species (ROS) accumulation elicited by different intrinsic stimuli (like metabolism), as well as external stimuli and age. Replicative senescence is mainly executed by telomere shortening, the activation of the p53/p16INK4/Rb molecular pathways, and chromatin remodeling. In addition, senescent cells produce and secrete a complex mixture of molecules, commonly known as the senescence-associated secretory phenotype (SASP), that regulate most of their non-cell-autonomous effects. In this review, we discuss the molecular and cellular mechanisms regulating different characteristics of the senescence phenotype and their consequences for adult CSCs in particular. Because senescent cells contribute to the outcome of a variety of cardiac diseases, including age-related and unrelated cardiac diseases like diabetic cardiomyopathy and anthracycline cardiotoxicity, therapies that target senescent cell clearance are actively being explored. Moreover, the further understanding of the reversibility of the senescence phenotype will help to develop novel rational therapeutic strategies.
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Affiliation(s)
- Eleonora Cianflone
- Department of Medical and Surgical Sciences, Magna Graecia University, 88100 Catanzaro, Italy;
| | - Michele Torella
- Department of Translational Medical Sciences, AORN dei Colli/Monaldi Hospital, University of Campania “L. Vanvitelli”, Via Leonardo Bianchi, 80131 Naples, Italy;
| | - Flavia Biamonte
- Department of Experimental and Clinical Medicine and Interdepartmental Centre of Services (CIS), Magna Graecia University, 88100 Catanzaro, Italy; (F.B.); (F.S.C.)
| | - Antonella De Angelis
- Department of Experimental Medicine, Section of Pharmacology, University of Campania “L.Vanvitelli”, 80121 Naples, Italy;
| | - Konrad Urbanek
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
| | - Francesco S. Costanzo
- Department of Experimental and Clinical Medicine and Interdepartmental Centre of Services (CIS), Magna Graecia University, 88100 Catanzaro, Italy; (F.B.); (F.S.C.)
| | - Marcello Rota
- Department of Physiology, New York Medical College, Valhalla, NY 10595, USA;
| | - Georgina M. Ellison-Hughes
- Centre for Human and Applied Physiological Sciences and Centre for Stem Cells and Regenerative Medicine, School of Basic and Medical Biosciences, Faculty of Life Sciences & Medicine, King’s College London, Guys Campus-Great Maze Pond rd, London SE1 1UL, UK;
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, Magna Graecia University, 88100 Catanzaro, Italy
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24
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Cell-based therapies for the treatment of myocardial infarction: lessons from cardiac regeneration and repair mechanisms in non-human vertebrates. Heart Fail Rev 2020; 24:133-142. [PMID: 30421074 DOI: 10.1007/s10741-018-9750-8] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Ischemic cardiomyopathy is the cardiovascular condition with the highest impact on the Western population. In mammals (humans included), prolonged ischemia in the ventricular walls causes the death of cardiomyocytes (myocardial infarction, MI). The loss of myocardial mass is soon compensated by the formation of a reparative, non-contractile fibrotic scar that ultimately affects heart performance. Despite the enormous clinical relevance of MI, no effective therapy is available for the long-term treatment of this condition. Moreover, since the human heart is not able to undergo spontaneous regeneration, many researchers aim at designing cell-based therapies that allow for the substitution of dead cardiomyocytes by new, functional ones. So far, the majority of such strategies rely on the injection of different progenitor/stem cells to the infarcted heart. These cardiovascular progenitors, which are expected to differentiate into cardiomyocytes de novo, seldom give rise to new cardiac muscle. In this context, the most important challenge in the field is to fully disclose the molecular and cellular mechanisms that could promote active myocardial regeneration after cardiac damage. Accordingly, we suggest that such strategy should be inspired by the unique regenerative and reparative responses displayed by non-human animal models, from the restricted postnatal myocardial regeneration abilities of the murine heart to the full ventricular regeneration of some bony fishes (e.g., zebrafish). In this review article, we will discuss about current scientific approaches to study cardiac reparative and regenerative phenomena using animal models.
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25
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Yellamilli A, Ren Y, McElmurry RT, Lambert JP, Gross P, Mohsin S, Houser SR, Elrod JW, Tolar J, Garry DJ, van Berlo JH. Abcg2-expressing side population cells contribute to cardiomyocyte renewal through fusion. FASEB J 2020; 34:5642-5657. [PMID: 32100368 DOI: 10.1096/fj.201902105r] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Revised: 02/10/2020] [Accepted: 02/13/2020] [Indexed: 12/15/2022]
Abstract
The adult mammalian heart has a limited regenerative capacity. Therefore, identification of endogenous cells and mechanisms that contribute to cardiac regeneration is essential for the development of targeted therapies. The side population (SP) phenotype has been used to enrich for stem cells throughout the body; however, SP cells isolated from the heart have been studied exclusively in cell culture or after transplantation, limiting our understanding of their function in vivo. We generated a new Abcg2-driven lineage-tracing mouse model with efficient labeling of SP cells. Labeled SP cells give rise to terminally differentiated cells in bone marrow and intestines. In the heart, labeled SP cells give rise to lineage-traced cardiomyocytes under homeostatic conditions with an increase in this contribution following cardiac injury. Instead of differentiating into cardiomyocytes like proposed cardiac progenitor cells, cardiac SP cells fuse with preexisting cardiomyocytes to stimulate cardiomyocyte cell cycle reentry. Our study is the first to show that fusion between cardiomyocytes and non-cardiomyocytes, identified by the SP phenotype, contribute to endogenous cardiac regeneration by triggering cardiomyocyte cell cycle reentry in the adult mammalian heart.
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Affiliation(s)
- Amritha Yellamilli
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA.,Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Yi Ren
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Ron T McElmurry
- Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Jonathan P Lambert
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Polina Gross
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Sadia Mohsin
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Steven R Houser
- Cardiovascular Research Center, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - John W Elrod
- Center for Translational Medicine, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA
| | - Jakub Tolar
- Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Pediatrics, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Daniel J Garry
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA
| | - Jop H van Berlo
- Lillehei Heart Institute, University of Minnesota Medical School, Minneapolis, MN, USA.,Department of Integrative Biology and Physiology, University of Minnesota Medical School, Minneapolis, MN, USA.,Stem Cell Institute, University of Minnesota Medical School, Minneapolis, MN, USA
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26
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Witman N, Zhou C, Grote Beverborg N, Sahara M, Chien KR. Cardiac progenitors and paracrine mediators in cardiogenesis and heart regeneration. Semin Cell Dev Biol 2019; 100:29-51. [PMID: 31862220 DOI: 10.1016/j.semcdb.2019.10.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2019] [Revised: 10/13/2019] [Accepted: 10/21/2019] [Indexed: 12/17/2022]
Abstract
The mammalian hearts have the least regenerative capabilities among tissues and organs. As such, heart regeneration has been and continues to be the ultimate goal in the treatment against acquired and congenital heart diseases. Uncovering such a long-awaited therapy is still extremely challenging in the current settings. On the other hand, this desperate need for effective heart regeneration has developed various forms of modern biotechnologies in recent years. These involve the transplantation of pluripotent stem cell-derived cardiac progenitors or cardiomyocytes generated in vitro and novel biochemical molecules along with tissue engineering platforms. Such newly generated technologies and approaches have been shown to effectively proliferate cardiomyocytes and promote heart repair in the diseased settings, albeit mainly preclinically. These novel tools and medicines give somehow credence to breaking down the barriers associated with re-building heart muscle. However, in order to maximize efficacy and achieve better clinical outcomes through these cell-based and/or cell-free therapies, it is crucial to understand more deeply the developmental cellular hierarchies/paths and molecular mechanisms in normal or pathological cardiogenesis. Indeed, the morphogenetic process of mammalian cardiac development is highly complex and spatiotemporally regulated by various types of cardiac progenitors and their paracrine mediators. Here we discuss the most recent knowledge and findings in cardiac progenitor cell biology and the major cardiogenic paracrine mediators in the settings of cardiogenesis, congenital heart disease, and heart regeneration.
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Affiliation(s)
- Nevin Witman
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Chikai Zhou
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden
| | - Niels Grote Beverborg
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Cardiology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands
| | - Makoto Sahara
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Surgery, Yale University School of Medicine, CT, USA.
| | - Kenneth R Chien
- Department of Cell and Molecular Biology, Karolinska Institutet, SE-171 77 Stockholm, Sweden; Department of Medicine, Karolinska Institutet, SE-171 77 Stockholm, Sweden.
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27
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Barreto S, Hamel L, Schiatti T, Yang Y, George V. Cardiac Progenitor Cells from Stem Cells: Learning from Genetics and Biomaterials. Cells 2019; 8:E1536. [PMID: 31795206 PMCID: PMC6952950 DOI: 10.3390/cells8121536] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 11/20/2019] [Accepted: 11/21/2019] [Indexed: 02/07/2023] Open
Abstract
Cardiac Progenitor Cells (CPCs) show great potential as a cell resource for restoring cardiac function in patients affected by heart disease or heart failure. CPCs are proliferative and committed to cardiac fate, capable of generating cells of all the cardiac lineages. These cells offer a significant shift in paradigm over the use of human induced pluripotent stem cell (iPSC)-derived cardiomyocytes owing to the latter's inability to recapitulate mature features of a native myocardium, limiting their translational applications. The iPSCs and direct reprogramming of somatic cells have been attempted to produce CPCs and, in this process, a variety of chemical and/or genetic factors have been evaluated for their ability to generate, expand, and maintain CPCs in vitro. However, the precise stoichiometry and spatiotemporal activity of these factors and the genetic interplay during embryonic CPC development remain challenging to reproduce in culture, in terms of efficiency, numbers, and translational potential. Recent advances in biomaterials to mimic the native cardiac microenvironment have shown promise to influence CPC regenerative functions, while being capable of integrating with host tissue. This review highlights recent developments and limitations in the generation and use of CPCs from stem cells, and the trends that influence the direction of research to promote better application of CPCs.
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Affiliation(s)
- Sara Barreto
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
| | | | - Teresa Schiatti
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
| | - Ying Yang
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
| | - Vinoj George
- Guy Hilton Research Centre, School of Pharmacy & Bioengineering, Keele University, Staffordshire ST4 7QB, UK; (S.B.); (T.S.); (Y.Y.)
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28
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Li Calzi S, Cook T, Della Rocca DG, Zhang J, Shenoy V, Yan Y, Espejo A, Rathinasabapathy A, Jacobsen MH, Salazar T, Sandusky GE, Shaw LC, March K, Raizada MK, Pepine CJ, Katovich MJ, Grant MB. Complementary Embryonic and Adult Cell Populations Enhance Myocardial Repair in Rat Myocardial Injury Model. Stem Cells Int 2019; 2019:3945850. [PMID: 31781239 PMCID: PMC6875168 DOI: 10.1155/2019/3945850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2018] [Revised: 04/09/2019] [Accepted: 10/01/2019] [Indexed: 11/18/2022] Open
Abstract
We compared the functional outcome of Isl-1+ cardiac progenitors, CD90+ bone marrow-derived progenitor cells, and the combination of the two in a rat myocardial infarction (MI) model. Isl-1+ cells were isolated from embryonic day 12.5 (E12.5) rat hearts and expanded in vitro. Thy-1+/CD90+ cells were isolated from the bone marrow of adult Sprague-Dawley rats by immunomagnetic cell sorting. Six-week-old female Sprague-Dawley rats underwent permanent left anterior descending (LAD) coronary artery ligation and received intramyocardial injection of either saline, Isl-1+ cells, CD90+ cells, or a combination of Isl-1+ and CD90+ cells, at the time of infarction. Cells were delivered transepicardially to the peri-infarct zone. Left ventricular function was assessed by transthoracic echocardiography at 1- and 4-week post-MI and by Millar catheterization (-dP/dt and +dP/dt) at 4-week post-MI. Fluorescence in situ hybridization (Isl-1+cells) and monochrystalline iron oxide nanoparticles labeling (MION; CD90+ cells) were performed to assess biodistribution of transplanted cells. Only the combination of cells demonstrated a significant improvement of cardiac function as assessed by anterior wall contractility, dP/dt (max), and dP/dt (min), compared to Isl-1+ or CD90+ cell monotherapies. In the combination cell group, viable cells were detected at week 4 when anterior wall motion was completely restored. In conclusion, the combination of Isl-1+ cardiac progenitors and adult bone marrow-derived CD90+ cells shows prolonged and robust myocardial tissue repair and provides support for the use of complementary cell populations to enhance myocardial repair.
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Affiliation(s)
- Sergio Li Calzi
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0001, USA
| | - Todd Cook
- Department of Medicine, IUPUI, Indianapolis, IN 46202, USA
| | | | - Juan Zhang
- Department of Pharmacodynamics, University of Florida, Gainesville, FL 32611, USA
| | - Vinayak Shenoy
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32611, USA
| | - Yuanqing Yan
- Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Andrew Espejo
- Department of Pharmacodynamics, University of Florida, Gainesville, FL 32611, USA
| | | | - Max H. Jacobsen
- Pathology and Laboratory Med., IUPUI, Indianapolis, IN 46202, USA
| | - Tatiana Salazar
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0001, USA
| | | | - Lynn C. Shaw
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0001, USA
| | - Keith March
- Department of Medicine, IUPUI, Indianapolis, IN 46202, USA
| | - Mohan K. Raizada
- Department of Physiology and Functional Genomics, University of Florida, Gainesville, FL 32611, USA
| | - Carl J. Pepine
- Department of Medicine, University of Florida, Gainesville, FL 32611, USA
| | - Michael J. Katovich
- Department of Pharmacodynamics, University of Florida, Gainesville, FL 32611, USA
| | - Maria B. Grant
- Department of Ophthalmology and Visual Sciences, University of Alabama at Birmingham, Birmingham, AL 35294-0001, USA
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29
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Mózner O, Bartos Z, Zámbó B, Homolya L, Hegedűs T, Sarkadi B. Cellular Processing of the ABCG2 Transporter-Potential Effects on Gout and Drug Metabolism. Cells 2019; 8:E1215. [PMID: 31597297 PMCID: PMC6830335 DOI: 10.3390/cells8101215] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2019] [Revised: 10/04/2019] [Accepted: 10/05/2019] [Indexed: 02/07/2023] Open
Abstract
The human ABCG2 is an important plasma membrane multidrug transporter, involved in uric acid secretion, modulation of absorption of drugs, and in drug resistance of cancer cells. Variants of the ABCG2 transporter, affecting cellular processing and trafficking, have been shown to cause gout and increased drug toxicity. In this paper, we overview the key cellular pathways involved in the processing and trafficking of large membrane proteins, focusing on ABC transporters. We discuss the information available for disease-causing polymorphic variants and selected mutations of ABCG2, causing increased degradation and impaired travelling of the transporter to the plasma membrane. In addition, we provide a detailed in silico analysis of an as yet unrecognized loop region of the ABCG2 protein, in which a recently discovered mutation may actually promote ABCG2 membrane expression. We suggest that post-translational modifications in this unstructured loop at the cytoplasmic surface of the protein may have special influence on ABCG2 processing and trafficking.
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Affiliation(s)
- Orsolya Mózner
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - Zsuzsa Bartos
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
| | - Boglárka Zámbó
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - László Homolya
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
| | - Tamás Hegedűs
- MTA-SE Molecular Biophysics Research Group, Hungarian Academy of Sciences, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
| | - Balázs Sarkadi
- Institute of Enzymology, Research Centre for Natural Sciences, Magyar Tudosok krt. 2, 1117 Budapest, Hungary.
- Department of Biophysics and Radiation Biology, Semmelweis University, Tűzoltó u. 37-47, 1094 Budapest, Hungary.
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30
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Zhang L, Sultana N, Yan J, Yang F, Chen F, Chepurko E, Yang FC, Du Q, Zangi L, Xu M, Bu L, Cai CL. Cardiac Sca-1 + Cells Are Not Intrinsic Stem Cells for Myocardial Development, Renewal, and Repair. Circulation 2019; 138:2919-2930. [PMID: 30566018 DOI: 10.1161/circulationaha.118.035200] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
BACKGROUND For more than a decade, Sca-1+ cells within the mouse heart have been widely recognized as a stem cell population with multipotency that can give rise to cardiomyocytes, endothelial cells, and smooth muscle cells in vitro and after cardiac grafting. However, the developmental origin and authentic nature of these cells remain elusive. METHODS Here, we used a series of high-fidelity genetic mouse models to characterize the identity and regenerative potential of cardiac resident Sca-1+ cells. RESULTS With these novel genetic tools, we found that Sca-1 does not label cardiac precursor cells during early embryonic heart formation. Postnatal cardiac resident Sca-1+ cells are in fact a pure endothelial cell population. They retain endothelial properties and exhibit minimal cardiomyogenic potential during development, normal aging and upon ischemic injury. CONCLUSIONS Our study provides definitive insights into the nature of cardiac resident Sca-1+ cells. The observations challenge the current dogma that cardiac resident Sca-1+ cells are intrinsic stem cells for myocardial development, renewal, and repair, and suggest that the mechanisms of transplanted Sca-1+ cells in heart repair need to be reassessed.
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Affiliation(s)
- Lu Zhang
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
| | - Nishat Sultana
- Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York.,Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Jianyun Yan
- Department of Cardiology, Laboratory of Heart Center, Zhujiang Hospital, Southern Medical University, Guangdong Provincial Biomedical Engineering Technology Research Center for Cardiovascular Disease, and Sino-Japanese Cooperation Platform for Translational Research in Heart Failure, Guangzhou, China (J.Y.)
| | - Fan Yang
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
| | - Fuxue Chen
- College of Life Sciences, Shanghai University, China (F.C.)
| | - Elena Chepurko
- Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Feng-Chun Yang
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Qinghua Du
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Lior Zangi
- Department of Medicine and Cardiovascular Research Center (N.S., E.C., L. Zangi), Icahn School of Medicine at Mount Sinai, New York
| | - Mingjiang Xu
- Department of Biochemistry and Molecular Biology, Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, FL (F.-C.Y., Q.D., M.X.)
| | - Lei Bu
- Leon H. Charney Division of Cardiology, New York University School of Medicine, New York, NY (L.B.)
| | - Chen-Leng Cai
- Riley Heart Research Center and Herman B. Wells Center for Pediatric Research, Indiana University School of Medicine, Indianapolis (L. Zhang, F.Y., C.-L.C.).,Department of Developmental and Regenerative Biology and The Black Family Stem Cell Institute (L. Zhang, N.S., F.Y., C.-L.C.), Icahn School of Medicine at Mount Sinai, New York
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31
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Yousefi M, Mamipour M, Sokullu SE, Ghaderi S, Amini H, Rahbarghazi R. Toll-like receptors in the functional orientation of cardiac progenitor cells. J Cell Physiol 2019; 234:19451-19463. [PMID: 31025370 DOI: 10.1002/jcp.28738] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 04/04/2019] [Accepted: 04/11/2019] [Indexed: 12/17/2022]
Abstract
Cardiac progenitor cells (CPCs) have the potential to differentiate into several cell lineages with the ability to restore in cardiac tissue. Multipotency and self-renewal activity are the crucial characteristics of CPCs. Also, CPCs have promising therapeutic roles in cardiac diseases such as valvular disease, thrombosis, atherosclerosis, congestive heart failure, and cardiac remodeling. Toll-like receptors (TLRs), as the main part of the innate immunity, have a key role in the development and differentiation of immune cells. Some reports are found regarding the effect of TLRs in the maturation of stem cells. This article tried to find the potential role of TLRs in the dynamics of CPCs. By showing possible crosstalk between the TLR signaling pathways and CPCs dynamics, we could achieve a better conception related to TLRs in the regeneration of cardiac tissue.
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Affiliation(s)
- Mohammadreza Yousefi
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Translational Medicine, Koç University, Istanbul, Turkey
| | - Mina Mamipour
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Research Center for Translational Medicine, Koç University, Istanbul, Turkey
| | - Sadiye E Sokullu
- Engineering Sciences, Bioengineering Department, Faculty of Engineering and Architecture, Izmir Katip Celebi University, Izmir, Turkey
| | - Shahrooz Ghaderi
- Department of System Physiology, Ruhr University, Bochum, Germany
| | - Hassan Amini
- Stem Cell Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of General and Vascular Surgery, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Reza Rahbarghazi
- Tuberculosis and Lung Disease Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Applied Cell Sciences, Faculty of Advanced Medical Sciences, Tabriz University of Medical Sciences, Tabriz, Iran
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32
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Lazzeri E, Angelotti ML, Conte C, Anders HJ, Romagnani P. Surviving Acute Organ Failure: Cell Polyploidization and Progenitor Proliferation. Trends Mol Med 2019; 25:366-381. [PMID: 30935780 DOI: 10.1016/j.molmed.2019.02.006] [Citation(s) in RCA: 64] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2018] [Revised: 02/09/2019] [Accepted: 02/13/2019] [Indexed: 12/20/2022]
Abstract
In acute organ failure, rapid compensation of function loss assures survival. Dedifferentiation and/or proliferation of surviving parenchymal cells could imply a transient (and potentially fatal) impairment of residual functional performance. However, evolution has selected two flexible life-saving mechanisms acting synergistically on organ function recovery. Sustaining residual performance is possible when the remnant differentiated parenchymal cells avoid cell division, but increase function by undergoing hypertrophy via endoreplication, leading to polyploid cells. In addition, tissue progenitors, representing a subset of less-differentiated and/or self-renewing parenchymal cells completing cytokinesis, proliferate and differentiate to regenerate lost parenchymal cells. Here, we review the evolving evidence on polyploidization and progenitor-driven regeneration in acute liver, heart, and kidney failure with evolutionary advantages and trade-offs in organ repair.
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Affiliation(s)
- Elena Lazzeri
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE)
| | - Maria Lucia Angelotti
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE)
| | - Carolina Conte
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE)
| | - Hans-Joachim Anders
- Medizinische Klinik und Poliklinik IV, Klinikum der LMU München, Munich, Germany
| | - Paola Romagnani
- Department of Biological and Experimental Medical Science 'Mario Serio', Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies (DENOTHE); Meyer Children's Hospital, Florence, Italy. http://www.twitter.com/PRomagnani
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Adult Cardiac Stem Cell Aging: A Reversible Stochastic Phenomenon? OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2019; 2019:5813147. [PMID: 30881594 PMCID: PMC6383393 DOI: 10.1155/2019/5813147] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/09/2018] [Accepted: 11/08/2018] [Indexed: 12/17/2022]
Abstract
Aging is by far the dominant risk factor for the development of cardiovascular diseases, whose prevalence dramatically increases with increasing age reaching epidemic proportions. In the elderly, pathologic cellular and molecular changes in cardiac tissue homeostasis and response to injury result in progressive deteriorations in the structure and function of the heart. Although the phenotypes of cardiac aging have been the subject of intense study, the recent discovery that cardiac homeostasis during mammalian lifespan is maintained and regulated by regenerative events associated with endogenous cardiac stem cell (CSC) activation has produced a crucial reconsideration of the biology of the adult and aged mammalian myocardium. The classical notion of the adult heart as a static organ, in terms of cell turnover and renewal, has now been replaced by a dynamic model in which cardiac cells continuously die and are then replaced by CSC progeny differentiation. However, CSCs are not immortal. They undergo cellular senescence characterized by increased ROS production and oxidative stress and loss of telomere/telomerase integrity in response to a variety of physiological and pathological demands with aging. Nevertheless, the old myocardium preserves an endogenous functionally competent CSC cohort which appears to be resistant to the senescent phenotype occurring with aging. The latter envisions the phenomenon of CSC ageing as a result of a stochastic and therefore reversible cell autonomous process. However, CSC aging could be a programmed cell cycle-dependent process, which affects all or most of the endogenous CSC population. The latter would infer that the loss of CSC regenerative capacity with aging is an inevitable phenomenon that cannot be rescued by stimulating their growth, which would only speed their progressive exhaustion. The resolution of these two biological views will be crucial to design and develop effective CSC-based interventions to counteract cardiac aging not only improving health span of the elderly but also extending lifespan by delaying cardiovascular disease-related deaths.
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Xu Y, Sun P, Wang JY, Li ZZ, Gao RL, Wang XZ, Phillips WD, Liang SX. Differentiation of CD45‑/CD31+ lung side population cells into endothelial and smooth muscle cells in vitro. Int J Mol Med 2019; 43:1128-1138. [PMID: 30628669 PMCID: PMC6365051 DOI: 10.3892/ijmm.2019.4053] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2018] [Accepted: 12/27/2018] [Indexed: 01/12/2023] Open
Abstract
Side population (SP) cells are a small subpopulation of cells found in many mammalian tissues and organs, identified by their capacity to efflux Hoechst 33342 dye. They are enriched for stem/progenitor cell activity. SP cells isolated from the adult mouse lung can be separated into a CD45+ subset (bone marrow-derived) and a CD45− subset that can be subdivided into CD31− and CD31+ subpopulations. CD45−/CD31− lung SP (LSP) cells are known to be mesenchymal stem cells. However, CD45−/CD31+ LSP cells are not fully characterized. In the present study, it was found that CD45−/CD31+ LSP cells were able to form colonies. Based on the expression of vascular endothelial growth factor receptor 2 (VEGFR2), these cells were separated into VEGFR2− and VEGFR2+ cells. The CD45−/CD31+/VEGFR2− LSP cells expressed genes characteristic of smooth muscle and endothelial progenitors, and were able to differentiate into smooth muscle and endothelial cells in vitro. The CD45−/CD31+/VEGFR2+ LSP cells expressed genes characteristic of endothelial progenitors and gave rise to endothelial cells, although not smooth muscle, in vitro. The data demonstrate that CD45−/CD31+/VEGFR2− LSP cells differentiated into CD45−/CD31+/VEGFR2+ LSP cells and then endothelial cells, indicating that CD45−/CD31+/VEGFR2+ LSP cells are likely to be derived from CD45−/CD31+/VEGFR2− LSP cells. Taken together, the results suggest that CD45−/CD31+ LSP cells can be separated into CD45−/CD31+/VEGFR2− LSP cells, which may be progenitors of endothelial and smooth muscle, whereas CD45−/CD31+/VEGFR2+ LSP cells may serve as late commitment endothelial progenitors in the adult mouse lung.
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Affiliation(s)
- Yang Xu
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Ping Sun
- Department of Hematology, Jining First People's Hospital, Jining, Shandong 272000, P.R. China
| | - Jian-Yu Wang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Zong-Ze Li
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
| | - Rui-Lan Gao
- Institution of Hematology Research, The First Affiliated Hospital of Zhejian Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xue-Zhe Wang
- Department of Clinical Laboratory, The First Affiliated Hospital of Jinzhou Medical University, Jinzhou, Liaoning 121001, P.R. China
| | - William D Phillips
- School of Medical Sciences (Physiology) and Bosch Institute, University of Sydney, Sydney, NSW 2006, Australia
| | - Simon X Liang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Jinzhou Medical University, Jinzhou, Liaoning 121000, P.R. China
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Marino F, Scalise M, Cianflone E, Mancuso T, Aquila I, Agosti V, Torella M, Paolino D, Mollace V, Nadal-Ginard B, Torella D. Role of c-Kit in Myocardial Regeneration and Aging. Front Endocrinol (Lausanne) 2019; 10:371. [PMID: 31275242 PMCID: PMC6593054 DOI: 10.3389/fendo.2019.00371] [Citation(s) in RCA: 47] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/22/2019] [Accepted: 05/24/2019] [Indexed: 12/15/2022] Open
Abstract
c-Kit, a type III receptor tyrosine kinase (RTK), is involved in multiple intracellular signaling whereby it is mainly considered a stem cell factor receptor, which participates in vital functions of the mammalian body, including the human. Furthermore, c-kit is a necessary yet not sufficient marker to detect and isolate several types of tissue-specific adult stem cells. Accordingly, c-kit was initially used as a marker to identify and enrich for adult cardiac stem/progenitor cells (CSCs) that were proven to be clonogenic, self-renewing and multipotent, being able to differentiate into cardiomyocytes, endothelial cells and smooth muscle cells in vitro as well as in vivo after myocardial injury. Afterwards it was demonstrated that c-kit expression labels a heterogenous cardiac cell population, which is mainly composed by endothelial cells while only a very small fraction represents CSCs. Furthermore, c-kit as a signaling molecule is expressed at different levels in this heterogenous c-kit labeled cardiac cell pool, whereby c-kit low expressers are enriched for CSCs while c-kit high expressers are endothelial and mast cells. This heterogeneity in cell composition and expression levels has been neglected in recent genetic fate map studies focusing on c-kit, which have claimed that c-kit identifies cells with robust endothelial differentiation potential but with minimal if not negligible myogenic commitment potential. However, modification of c-kit gene for Cre Recombinase expression in these Cre/Lox genetic fate map mouse models produced a detrimental c-kit haploinsufficiency that prevents efficient labeling of true CSCs on one hand while affecting the regenerative potential of these cells on the other. Interestingly, c-kit haploinsufficiency in c-kit-deficient mice causes a worsening myocardial repair after injury and accelerates cardiac aging. Therefore, these studies have further demonstrated that adult c-kit-labeled CSCs are robustly myogenic and that the adult myocardium relies on c-kit expression to regenerate after injury and to counteract aging effects on cardiac structure and function.
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Affiliation(s)
- Fabiola Marino
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- Department of Health Sciences, Interregional Research Center on Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Mariangela Scalise
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Eleonora Cianflone
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Teresa Mancuso
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Valter Agosti
- Interdepartmental Center of Services (CIS) of Genomics, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Sciences, University of Campania L. Vanvitelli, Naples, Italy
| | - Donatella Paolino
- Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
| | - Vincenzo Mollace
- Department of Health Sciences, Interregional Research Center on Food Safety and Health (IRC-FSH), University Magna Graecia of Catanzaro, Catanzaro, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- StemCell OpCo, Madrid, Spain
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Experimental and Clinical Medicine, University Magna Graecia, Catanzaro, Italy
- *Correspondence: Daniele Torella
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Scalise M, Marino F, Cianflone E, Mancuso T, Marotta P, Aquila I, Torella M, Nadal-Ginard B, Torella D. Heterogeneity of Adult Cardiac Stem Cells. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1169:141-178. [PMID: 31487023 DOI: 10.1007/978-3-030-24108-7_8] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Abstract
Cardiac biology and heart regeneration have been intensively investigated and debated in the last 15 years. Nowadays, the well-established and old dogma that the adult heart lacks of any myocyte-regenerative capacity has been firmly overturned by the evidence of cardiomyocyte renewal throughout the mammalian life as part of normal organ cell homeostasis, which is increased in response to injury. Concurrently, reproducible evidences from independent laboratories have convincingly shown that the adult heart possesses a pool of multipotent cardiac stem/progenitor cells (CSCs or CPCs) capable of sustaining cardiomyocyte and vascular tissue refreshment after injury. CSC transplantation in animal models displays an effective regenerative potential and may be helpful to treat chronic heart failure (CHF), obviating at the poor/modest results using non-cardiac cells in clinical trials. Nevertheless, the degree/significance of cardiomyocyte turnover in the adult heart, which is insufficient to regenerate extensive damage from ischemic and non-ischemic origin, remains strongly disputed. Concurrently, different methodologies used to detect CSCs in situ have created the paradox of the adult heart harboring more than seven different cardiac progenitor populations. The latter was likely secondary to the intrinsic heterogeneity of any regenerative cell agent in an adult tissue but also to the confusion created by the heterogeneity of the cell population identified by a single cell marker used to detect the CSCs in situ. On the other hand, some recent studies using genetic fate mapping strategies claimed that CSCs are an irrelevant endogenous source of new cardiomyocytes in the adult. On the basis of these contradictory findings, here we critically reviewed the available data on adult CSC biology and their role in myocardial cell homeostasis and repair.
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Affiliation(s)
- Mariangela Scalise
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Fabiola Marino
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Eleonora Cianflone
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Teresa Mancuso
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Pina Marotta
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Surgery, University of Campania "L.Vanvitelli", Naples, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology Laboratory, Department of Experimental and Clinical Medicine, Magna Graecia University, Catanzaro, Italy.
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Side Population: Its Use in the Study of Cellular Heterogeneity and as a Potential Enrichment Tool for Rare Cell Populations. Stem Cells Int 2018; 2018:2472137. [PMID: 30627171 PMCID: PMC6304857 DOI: 10.1155/2018/2472137] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/24/2018] [Revised: 11/07/2018] [Accepted: 11/14/2018] [Indexed: 12/16/2022] Open
Abstract
There is still much to learn about the cells used for cell- and gene-based therapies in the clinical setting. Stem cells are found in virtually all tissues in the human body. As a result, cells isolated from these tissues are a heterogeneous population consisting of various subpopulations including stem cells. Several strategies have been used to isolate and define the subpopulations that constitute these heterogeneous populations, one of which is the side population (SP) assay. SP cells are identified by their ability to efflux a fluorescent dye at a rate that is greater than the main cell population. This elevated rate of dye efflux has been attributed to the expression of members of the ATP-binding cassette (ABC) transporter protein family. SP cells have been identified in various tissues. In this review, we discuss the research to date on SP cells, focussing on SP cells identified in haematopoietic stem cells, adipose-derived stromal cells, and dental pulp.
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Sayed A, Valente M, Sassoon D. Does cardiac development provide heart research with novel therapeutic approaches? F1000Res 2018; 7. [PMID: 30450195 PMCID: PMC6221076 DOI: 10.12688/f1000research.15609.1] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 10/24/2018] [Indexed: 01/04/2023] Open
Abstract
Embryonic heart progenitors arise at specific spatiotemporal periods that contribute to the formation of distinct cardiac structures. In mammals, the embryonic and fetal heart is hypoxic by comparison to the adult heart. In parallel, the cellular metabolism of the cardiac tissue, including progenitors, undergoes a glycolytic to oxidative switch that contributes to cardiac maturation. While oxidative metabolism is energy efficient, the glycolytic-hypoxic state may serve to maintain cardiac progenitor potential. Consistent with this proposal, the adult epicardium has been shown to contain a reservoir of quiescent cardiac progenitors that are activated in response to heart injury and are hypoxic by comparison to adjacent cardiac tissues. In this review, we discuss the development and potential of the adult epicardium and how this knowledge may provide future therapeutic approaches for cardiac repair.
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Affiliation(s)
- Angeliqua Sayed
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
| | - Mariana Valente
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
| | - David Sassoon
- Cellular, Molecular, and Physiological Mechanisms of Heart Failure, Paris-Cardiovascular Research Center (PARCC), European Georges Pompidou Hospital (HEGP), INSERM U970, F-75737 Paris Cedex 15, Paris, France
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Rafatian G, Davis DR. Concise Review: Heart-Derived Cell Therapy 2.0: Paracrine Strategies to Increase Therapeutic Repair of Injured Myocardium. Stem Cells 2018; 36:1794-1803. [PMID: 30171743 DOI: 10.1002/stem.2910] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2018] [Revised: 08/13/2018] [Accepted: 08/20/2018] [Indexed: 01/09/2023]
Abstract
Despite progress in cardiovascular medicine, the incidence of heart failure is rising and represents a growing challenge. To address this, ex vivo proliferated heart-derived cell products have emerged as a promising investigational cell-treatment option. Despite being originally proposed as a straightforward myocyte replacement strategy, emerging evidence has shown that cell-mediated gains in cardiac function are leveraged on paracrine stimulation of endogenous repair and tissue salvage. In this concise review, we focus on the paracrine repertoire of heart-derived cells and outline strategies used to boost cell potency by targeting cytokines, metabolic preconditioning and supportive biomaterials. Mechanistic insights from these studies will shape future efforts to use defined factors and/or synthetic cell approaches to help the millions of patients worldwide suffering from heart failure. Stem Cells 2018;36:1794-10.
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Affiliation(s)
- Ghazaleh Rafatian
- Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Darryl R Davis
- Division of Cardiology, Department of Medicine, University of Ottawa Heart Institute, Ottawa, Ontario, Canada
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40
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Pogontke C, Guadix JA, Ruiz-Villalba A, Pérez-Pomares JM. Development of the Myocardial Interstitium. Anat Rec (Hoboken) 2018; 302:58-68. [PMID: 30288955 DOI: 10.1002/ar.23915] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 04/26/2018] [Accepted: 05/11/2018] [Indexed: 12/24/2022]
Abstract
The space between cardiac myocytes is commonly referred-to as the cardiac interstitium (CI). The CI is a unique, complex and dynamic microenvironment in which multiple cell types, extracellular matrix molecules, and instructive signals interact to crucially support heart homeostasis and promote cardiac responses to normal and pathologic stimuli. Despite the biomedical and clinical relevance of the CI, its detailed cellular structure remains to be elucidated. In this review, we will dissect the organization of the cardiac interstitium by following its changing cellular and molecular composition from embryonic developmental stages to adulthood, providing a systematic analysis of the biological components of the CI. The main goal of this review is to contribute to our understanding of the CI roles in health and disease. Anat Rec, 302:58-68, 2019. © 2018 Wiley Periodicals, Inc.
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Affiliation(s)
- Cristina Pogontke
- Department of Animal Biology, Faculty of Sciences, University of Málaga, Instituto Malagueño de Biomedicina (IBIMA), Campus de Teatinos s/n, 29080, Málaga, Spain.,BIONAND, Centro Andaluz de Nanomedicina y Biotecnología (Junta de Andalucía, Universidad de Málaga), Severo Ochoa n°25, 29590 Campanillas (Málaga), Spain
| | - Juan A Guadix
- Department of Animal Biology, Faculty of Sciences, University of Málaga, Instituto Malagueño de Biomedicina (IBIMA), Campus de Teatinos s/n, 29080, Málaga, Spain.,BIONAND, Centro Andaluz de Nanomedicina y Biotecnología (Junta de Andalucía, Universidad de Málaga), Severo Ochoa n°25, 29590 Campanillas (Málaga), Spain
| | - Adrián Ruiz-Villalba
- Stem Cell Therapy Area, Foundation for Applied Medical Research (CIMA), University of Navarra, Pamplona, Spain
| | - José M Pérez-Pomares
- Department of Animal Biology, Faculty of Sciences, University of Málaga, Instituto Malagueño de Biomedicina (IBIMA), Campus de Teatinos s/n, 29080, Málaga, Spain.,BIONAND, Centro Andaluz de Nanomedicina y Biotecnología (Junta de Andalucía, Universidad de Málaga), Severo Ochoa n°25, 29590 Campanillas (Málaga), Spain
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Jara Avaca M, Gruh I. Bioengineered Cardiac Tissue Based on Human Stem Cells for Clinical Application. ADVANCES IN BIOCHEMICAL ENGINEERING/BIOTECHNOLOGY 2018; 163:117-146. [PMID: 29218360 DOI: 10.1007/10_2017_24] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Engineered cardiac tissue might enable novel therapeutic strategies for the human heart in a number of acquired and congenital diseases. With recent advances in stem cell technologies, namely the availability of pluripotent stem cells, the generation of potentially autologous tissue grafts has become a realistic option. Nevertheless, a number of limitations still have to be addressed before clinical application of engineered cardiac tissue based on human stem cells can be realized. We summarize current progress and pending challenges regarding the optimal cell source, cardiomyogenic lineage specification, purification, safety of genetic cell engineering, and genomic stability. Cardiac cells should be combined with clinical grade scaffold materials for generation of functional myocardial tissue in vitro. Scale-up to clinically relevant dimensions is mandatory, and tissue vascularization is most probably required both for preclinical in vivo testing in suitable large animal models and for clinical application. Graphical Abstract.
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Affiliation(s)
- Monica Jara Avaca
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department for Cardiothoracic, Vascular and Transplantation Surgery (HTTG), Hannover Medical School (MHH) & Cluster of Excellence REBIRTH, Hannover, Germany
| | - Ina Gruh
- Leibniz Research Laboratories for Biotechnology and Artificial Organs (LEBAO), Department for Cardiothoracic, Vascular and Transplantation Surgery (HTTG), Hannover Medical School (MHH) & Cluster of Excellence REBIRTH, Hannover, Germany.
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42
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Langrzyk A, Nowak WN, Stępniewski J, Jaźwa A, Florczyk-Soluch U, Józkowicz A, Dulak J. Critical View on Mesenchymal Stromal Cells in Regenerative Medicine. Antioxid Redox Signal 2018; 29:169-190. [PMID: 28874054 DOI: 10.1089/ars.2017.7159] [Citation(s) in RCA: 30] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
SIGNIFICANCE The belief in the potency of stem cells has resulted in the medical applications of numerous cell types for organ repair, often with the low adherence to methodological stringency. Such uncritical enthusiasm is mainly presented in the approaches employing so-called mesenchymal stem cells (MSC), for the treatment of numerous, unrelated conditions. However, it should be stressed that such broad clinical applications of MSC are mostly based on the belief that MSC can efficiently differentiate into multiple cell types, not only osteoblasts, chondrocytes and adipose cells. Recent Advances: Studies employing lineage tracing established more promising markers to characterize MSC identity and localization in vivo and confirmed the differences between MSC isolated from various organs. Furthermore, preclinical and clinical experiments proved that transdifferentiation of MSC is unlikely to contribute to repair of numerous tissues, including the heart. Therefore, the salvage hypotheses, like MSC fusion with cells in target organs or the paracrine mechanisms, were proposed to justify the widespread application of MSC and to explain transient, if any, effects. CRITICAL ISSUES The lack of standardization concerning the cells markers, their origin and particularly the absence of stringent functional characterization of MSC, leads to propagation of the worrying hype despite the lack of convincing therapeutic efficiency of MSC. FUTURE DIRECTIONS The adherence to rigorous methodological rules is necessary to prevent the application of procedures which can be dangerous for patients and scientific research on the medical application of stem cells. Antioxid. Redox Signal. 00, 000-000.
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Affiliation(s)
| | - Witold N Nowak
- 2 Cardiovascular Division, King's College London , London, United Kingdom .,3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Jacek Stępniewski
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Agnieszka Jaźwa
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Urszula Florczyk-Soluch
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Alicja Józkowicz
- 3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
| | - Józef Dulak
- 1 Kardio-Med Silesia , Zabrze, Poland .,3 Department of Medical Biotechnology, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University , Kraków, Poland
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43
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Boffito M, Di Meglio F, Mozetic P, Giannitelli SM, Carmagnola I, Castaldo C, Nurzynska D, Sacco AM, Miraglia R, Montagnani S, Vitale N, Brancaccio M, Tarone G, Basoli F, Rainer A, Trombetta M, Ciardelli G, Chiono V. Surface functionalization of polyurethane scaffolds mimicking the myocardial microenvironment to support cardiac primitive cells. PLoS One 2018; 13:e0199896. [PMID: 29979710 PMCID: PMC6034803 DOI: 10.1371/journal.pone.0199896] [Citation(s) in RCA: 35] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2017] [Accepted: 06/15/2018] [Indexed: 11/28/2022] Open
Abstract
Scaffolds populated with human cardiac progenitor cells (CPCs) represent a therapeutic opportunity for heart regeneration after myocardial infarction. In this work, square-grid scaffolds are prepared by melt-extrusion additive manufacturing from a polyurethane (PU), further subjected to plasma treatment for acrylic acid surface grafting/polymerization and finally grafted with laminin-1 (PU-LN1) or gelatin (PU-G) by carbodiimide chemistry. LN1 is a cardiac niche extracellular matrix component and plays a key role in heart formation during embryogenesis, while G is a low-cost cell-adhesion protein, here used as a control functionalizing molecule. X-ray photoelectron spectroscopy analysis shows nitrogen percentage increase after functionalization. O1s and C1s core-level spectra and static contact angle measurements show changes associated with successful functionalization. ELISA assay confirms LN1 surface grafting. PU-G and PU-LN1 scaffolds both improve CPC adhesion, but LN1 functionalization is superior in promoting proliferation, protection from apoptosis and expression of differentiation markers for cardiomyocytes, endothelial and smooth muscle cells. PU-LN1 and PU scaffolds are biodegraded into non-cytotoxic residues. Scaffolds subcutaneously implanted in mice evoke weak inflammation and integrate with the host tissue, evidencing a significant blood vessel density around the scaffolds. PU-LN1 scaffolds show their superiority in driving CPC behavior, evidencing their promising role in myocardial regenerative medicine.
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Affiliation(s)
- Monica Boffito
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Franca Di Meglio
- Department of Public Health, University of Naples ‘Federico II’, Naples, Italy
| | - Pamela Mozetic
- Department of Engineering, Tissue Engineering Unit, Università Campus Bio-Medico di Roma, Rome, Italy
- Center for Translational Medicine, International Clinical Research Center, St.Anne’s University Hospital, Brno, Czechia
| | - Sara Maria Giannitelli
- Department of Engineering, Tissue Engineering Unit, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Irene Carmagnola
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Clotilde Castaldo
- Department of Public Health, University of Naples ‘Federico II’, Naples, Italy
| | - Daria Nurzynska
- Department of Public Health, University of Naples ‘Federico II’, Naples, Italy
| | - Anna Maria Sacco
- Department of Public Health, University of Naples ‘Federico II’, Naples, Italy
| | - Rita Miraglia
- Department of Public Health, University of Naples ‘Federico II’, Naples, Italy
| | - Stefania Montagnani
- Department of Public Health, University of Naples ‘Federico II’, Naples, Italy
| | - Nicoletta Vitale
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Mara Brancaccio
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Guido Tarone
- Department of Molecular Biotechnology and Health Sciences, University of Turin, Turin, Italy
| | - Francesco Basoli
- Department of Engineering, Tissue Engineering Unit, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Alberto Rainer
- Department of Engineering, Tissue Engineering Unit, Università Campus Bio-Medico di Roma, Rome, Italy
- Institute for Photonics and Nanotechnology, National Research Council, Rome, Italy
| | - Marcella Trombetta
- Department of Engineering, Tissue Engineering Unit, Università Campus Bio-Medico di Roma, Rome, Italy
| | - Gianluca Ciardelli
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
| | - Valeria Chiono
- Department of Mechanical and Aerospace Engineering, Politecnico di Torino, Turin, Italy
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44
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Abstract
Some of the most significant leaps in the history of modern civilization-the development of article in China, the steam engine, which led to the European industrial revolution, and the era of computers-have occurred when science converged with engineering. Recently, the convergence of human pluripotent stem cell technology with biomaterials and bioengineering have launched a new medical innovation: functional human engineered tissue, which promises to revolutionize the treatment of failing organs including most critically, the heart. This compendium covers recent, state-of-the-art developments in the fields of cardiovascular tissue engineering, as well as the needs and challenges associated with the clinical use of these technologies. We have not attempted to provide an exhaustive review in stem cell biology and cardiac cell therapy; many other important and influential reports are certainly merit but already been discussed in several recent reviews. Our scope is limited to the engineered tissues that have been fabricated to repair or replace components of the heart (eg, valves, vessels, contractile tissue) that have been functionally compromised by diseases or developmental abnormalities. In particular, we have focused on using an engineered myocardial tissue to mitigate deficiencies in contractile function.
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Affiliation(s)
- Jianyi Zhang
- From the Department of Biomedical Engineering, School of Medicine and School of Engineering, The University of Alabama at Birmingham (J.Z., W.Z.)
| | - Wuqiang Zhu
- From the Department of Biomedical Engineering, School of Medicine and School of Engineering, The University of Alabama at Birmingham (J.Z., W.Z.)
| | - Milica Radisic
- Department of Chemical Engineering and Applied Chemistry, Institute of Biomaterials and Biomedical Engineering, University of Toronto, Canada (M.R.)
| | - Gordana Vunjak-Novakovic
- Department of Biomedical Engineering and Department of Medicine, Columbia University, New York, NY (G.V.-N.)
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45
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Cianflone E, Aquila I, Scalise M, Marotta P, Torella M, Nadal-Ginard B, Torella D. Molecular basis of functional myogenic specification of Bona Fide multipotent adult cardiac stem cells. Cell Cycle 2018; 17:927-946. [PMID: 29862928 PMCID: PMC6103696 DOI: 10.1080/15384101.2018.1464852] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2018] [Revised: 06/01/2018] [Accepted: 04/08/2018] [Indexed: 01/14/2023] Open
Abstract
Ischemic Heart Disease (IHD) remains the developed world's number one killer. The improved survival from Acute Myocardial Infarction (AMI) and the progressive aging of western population brought to an increased incidence of chronic Heart Failure (HF), which assumed epidemic proportions nowadays. Except for heart transplantation, all treatments for HF should be considered palliative because none of the current therapies can reverse myocardial degeneration responsible for HF syndrome. To stop the HF epidemic will ultimately require protocols to reduce the progressive cardiomyocyte (CM) loss and to foster their regeneration. It is now generally accepted that mammalian CMs renew throughout life. However, this endogenous regenerative reservoir is insufficient to repair the extensive damage produced by AMI/IHD while the source and degree of CM turnover remains strongly disputed. Independent groups have convincingly shown that the adult myocardium harbors bona-fide tissue specific cardiac stem cells (CSCs). Unfortunately, recent reports have challenged the identity and the endogenous myogenic capacity of the c-kit expressing CSCs. This has hampered progress and unless this conflict is settled, clinical tests of repair/regenerative protocols are unlikely to provide convincing answers about their clinical potential. Here we review recent data that have eventually clarified the specific phenotypic identity of true multipotent CSCs. These cells when coaxed by embryonic cardiac morphogens undergo a precisely orchestrated myogenic commitment process robustly generating bona-fide functional cardiomyocytes. These data should set the path for the revival of further investigation untangling the regenerative biology of adult CSCs to harness their potential for HF prevention and treatment.
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Affiliation(s)
- Eleonora Cianflone
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Iolanda Aquila
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Mariangela Scalise
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Pina Marotta
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Michele Torella
- Department of Cardiothoracic Sciences, University of Campania Campus “Salvatore Venuta” Viale Europa- Loc. Germaneto “L. Vanvitelli”, Naples, Italy
| | - Bernardo Nadal-Ginard
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
| | - Daniele Torella
- Molecular and Cellular Cardiology, Department of Medical and Surgical Sciences, Magna Graecia University, Catanzaro, Italy
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46
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Romano N, Ceci M. The face of epicardial and endocardial derived cells in zebrafish. Exp Cell Res 2018; 369:166-175. [PMID: 29807022 DOI: 10.1016/j.yexcr.2018.05.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2018] [Revised: 05/15/2018] [Accepted: 05/21/2018] [Indexed: 02/09/2023]
Abstract
Zebrafish hearts can regenerate through activation of growth factors and trans-differentiation of fibroblasts, epicardial, myocardial and endocardial cells, all positive for GATA4 during the process. A possible model of regeneration of the whole heart and the regenerating cells in ex-vivo culture is presented here by a stimulation of cocktail of growth factors. In ex-vivo growth-factors-supplemented culture the heart regeneration was quite complete without signs of fibrosis. Epicardial- and endocardial-derived cells have been analyzed by electron microscopy evidencing two main types: 1) larger/prismatic and 2) small/rounded. Type (1) showed on the surface protein-sculptures, while type(2) was smooth with sparse globular proteins. To confirm their nature we have contemporarily analyzed their proliferative capability and markers-positivity. The cells treated by growth factors have at least two-fold more proliferation with GATA4-positivity. The type (1) cell evidenced WT1+(marker of embryonic epicardium); the type (2) showed NFTA2+(marker of embryonic endocardium); whereas cTNT-cardiotroponin was negative. Under growth factors stimulation, GATA4+/WT1+ and GATA4+/NFTA2+ could be suitable candidates to be the cells with capability to move in/out of the tissue, probably by using their integrins, and it opens the possibility to have long term selected culture to future characterization.
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Affiliation(s)
- Nicla Romano
- Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy.
| | - Marcello Ceci
- Department of Ecological and Biological Sciences, University of Tuscia, Viterbo, Italy
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47
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Lázár E, Sadek HA, Bergmann O. Cardiomyocyte renewal in the human heart: insights from the fall-out. Eur Heart J 2018; 38:2333-2342. [PMID: 28810672 DOI: 10.1093/eurheartj/ehx343] [Citation(s) in RCA: 103] [Impact Index Per Article: 14.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2017] [Accepted: 05/31/2017] [Indexed: 01/09/2023] Open
Abstract
The capacity of the mammalian heart to regenerate cardiomyocytes has been debated over the last decades. However, limitations in existing techniques to track and identify nascent cardiomyocytes have often led to inconsistent results. Radiocarbon (14C) birth dating, in combination with other quantitative strategies, allows to establish the number and age of human cardiomyocytes, making it possible to describe their age distribution and turnover dynamics. Accurate estimates of cardiomyocyte generation in the adult heart can provide the foundation for novel regenerative strategies that aim to stimulate cardiomyocyte renewal in various cardiac pathologies.
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Affiliation(s)
- Eniko Lázár
- Department of Cell and Molecular Biology, Karolinska Institute, Berzelius väg 35, Stockholm SE 171 65, Sweden
| | - Hesham A Sadek
- Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.,Center for Regenerative Science and Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA
| | - Olaf Bergmann
- Department of Cell and Molecular Biology, Karolinska Institute, Berzelius väg 35, Stockholm SE 171 65, Sweden.,DFG-Center for Regenerative Therapies, Technische Universität Dresden, Fetscherstraße 105, Dresden, D-01307, Germany
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48
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Vigneault P, Naud P, Qi X, Xiao J, Villeneuve L, Davis DR, Nattel S. Calcium-dependent potassium channels control proliferation of cardiac progenitor cells and bone marrow-derived mesenchymal stem cells. J Physiol 2018; 596:2359-2379. [PMID: 29574723 DOI: 10.1113/jp275388] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 02/26/2018] [Indexed: 12/26/2022] Open
Abstract
KEY POINTS Ex vivo proliferated c-Kit+ endogenous cardiac progenitor cells (eCPCs) obtained from mouse and human cardiac tissues have been reported to express a wide range of functional ion channels. In contrast to previous reports in cultured c-Kit+ eCPCs, we found that ion currents were minimal in freshly isolated cells. However, inclusion of free Ca2+ intracellularly revealed a prominent inwardly rectifying current identified as the intermediate conductance Ca2+ -activated K+ current (KCa3.1) Electrical function of both c-Kit+ eCPCs and bone marrow-derived mesenchymal stem cells is critically governed by KCa3.1 calcium-dependent potassium channels. Ca2+ -induced increases in KCa3.1 conductance are necessary to optimize membrane potential during Ca2+ entry. Membrane hyperpolarization due to KCa3.1 activation maintains the driving force for Ca2+ entry that activates stem cell proliferation. Cardiac disease downregulates KCa3.1 channels in resident cardiac progenitor cells. Alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine. ABSTRACT Endogenous c-Kit+ cardiac progenitor cells (eCPCs) and bone marrow (BM)-derived mesenchymal stem cells (MSCs) are being developed for cardiac regenerative therapy, but a better understanding of their physiology is needed. Here, we addressed the unknown functional role of ion channels in freshly isolated eCPCs and expanded BM-MSCs using patch-clamp, microfluorometry and confocal microscopy. Isolated c-Kit+ eCPCs were purified from dog hearts by immunomagnetic selection. Ion currents were barely detectable in freshly isolated c-Kit+ eCPCs with buffering of intracellular calcium (Ca2+i ). Under conditions allowing free intracellular Ca2+ , freshly isolated c-Kit+ eCPCs and ex vivo proliferated BM-MSCs showed prominent voltage-independent conductances that were sensitive to intermediate-conductance K+ -channel (KCa3.1 current, IKCa3.1 ) blockers and corresponding gene (KCNN4)-expression knockdown. Depletion of Ca2+i induced membrane-potential (Vmem ) depolarization, while store-operated Ca2+ entry (SOCE) hyperpolarized Vmem in both cell types. The hyperpolarizing SOCE effect was substantially reduced by IKCa3.1 or SOCE blockade (TRAM-34, 2-APB), and IKCa3.1 blockade (TRAM-34) or KCNN4-knockdown decreased the Ca2+ entry resulting from SOCE. IKCa3.1 suppression reduced c-Kit+ eCPC and BM-MSC proliferation, while significantly altering the profile of cyclin expression. IKCa3.1 was reduced in c-Kit+ eCPCs isolated from dogs with congestive heart failure (CHF), along with corresponding KCNN4 mRNA. Under perforated-patch conditions to maintain physiological [Ca2+ ]i , c-Kit+ eCPCs from CHF dogs had less negative resting membrane potentials (-58 ± 7 mV) versus c-Kit+ eCPCs from control dogs (-73 ± 3 mV, P < 0.05), along with slower proliferation. Our study suggests that Ca2+ -induced increases in IKCa3.1 are necessary to optimize membrane potential during the Ca2+ entry that activates progenitor cell proliferation, and that alterations in KCa3.1 may have pathophysiological and therapeutic significance in regenerative medicine.
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Affiliation(s)
- Patrick Vigneault
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Patrice Naud
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Xiaoyan Qi
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Jiening Xiao
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Louis Villeneuve
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada
| | - Darryl R Davis
- University of Ottawa Heart Institute, Ottawa, Ontario, Canada
| | - Stanley Nattel
- Research Center and Department of Medicine, Montreal Heart Institute, Université de Montréal, Montreal, Quebec, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada.,Institute of Pharmacology, West German Heart and Vascular Center, Faculty of Medicine, University Duisburg-Essen, Essen, Germany
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49
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Recent advances and perspectives on capture and concentration of label-free rare cells for biomedical science and engineering research. J Taiwan Inst Chem Eng 2018. [DOI: 10.1016/j.jtice.2018.02.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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50
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Abstract
Major cardiovascular events including myocardial infarction (MI) continue to dominate morbidity rates in the developed world. Although multiple device therapies and various pharmacological agents have been shown to improve patient care and reduce mortality rates, clinicians and researchers alike still lack a true panacea to regenerate damaged cardiac tissue. Over the previous two to three decades, cardiovascular stem cell therapies have held great promise. Several stem cell-based approaches have now been shown to improve ventricular function and are documented in preclinical animal models as well as phase I and phase II clinical trials. More recently, the cardiac progenitor cell has begun to gain momentum as an ideal candidate for stem cell therapy in heart disease. Here, we will highlight the most recent advances in cardiac stem/progenitor cell biology in regard to both the basics and applied settings.
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