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1
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Lee WS, Abel ED, Kim J. New Insights into IGF-1 Signaling in the Heart. Physiology (Bethesda) 2024; 39:0. [PMID: 38713091 DOI: 10.1152/physiol.00003.2024] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/10/2024] [Revised: 04/24/2024] [Accepted: 05/04/2024] [Indexed: 05/08/2024] Open
Abstract
Insulin-like growth factor-1 (IGF-1) signaling has multiple physiological roles in cellular growth, metabolism, and aging. Myocardial hypertrophy, cell death, senescence, fibrosis, and electrical remodeling are hallmarks of various heart diseases and contribute to the progression of heart failure. This review highlights the critical role of IGF-1 and its cognate receptor in cardiac hypertrophy, aging, and remodeling.
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Affiliation(s)
- Wang-Soo Lee
- Division of Cardiology, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
| | - E Dale Abel
- Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States
| | - Jaetaek Kim
- Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, Chung-Ang University, Seoul, Republic of Korea
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2
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Rao KS, Kloppenburg JE, Marquis T, Solomon L, McElroy-Yaggy KL, Spees JL. CTGF-D4 Amplifies LRP6 Signaling to Promote Grafts of Adult Epicardial-derived Cells That Improve Cardiac Function After Myocardial Infarction. Stem Cells 2022; 40:204-214. [PMID: 35257185 PMCID: PMC9199845 DOI: 10.1093/stmcls/sxab016] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2017] [Accepted: 11/24/2020] [Indexed: 01/26/2023]
Abstract
Transplantation of stem/progenitor cells holds promise for cardiac regeneration in patients with myocardial infarction (MI). Currently, however, low cell survival and engraftment after transplantation present a major barrier to many forms of cell therapy. One issue is that ligands, receptors, and signaling pathways that promote graft success remain poorly understood. Here, we prospectively isolate uncommitted epicardial cells from the adult heart surface by CD104 (β-4 integrin) and demonstrate that C-terminal peptide from connective tissue growth factor (CTGF-D4), when combined with insulin, effectively primes epicardial-derived cells (EPDC) for cardiac engraftment after MI. Similar to native epicardial derivatives that arise from epicardial EMT at the heart surface, the grafted cells migrated into injured myocardial tissue in a rat model of MI with reperfusion. By echocardiography, at 1 month after MI, we observed significant improvement in cardiac function for animals that received epicardial cells primed with CTGF-D4/insulin compared with those that received vehicle-primed (control) cells. In the presence of insulin, CTGF-D4 treatment significantly increased the phosphorylation of Wnt co-receptor LRP6 on EPDC. Competitive engraftment assays and neutralizing/blocking studies showed that LRP6 was required for EPDC engraftment after transplantation. Our results identify LRP6 as a key target for increasing EPDC engraftment after MI and suggest amplification of LRP6 signaling with CTGF-D4/insulin, or by other means, may provide an effective approach for achieving successful cellular grafts in regenerative medicine.
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Affiliation(s)
- Krithika S Rao
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
- Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA
| | - Jessica E Kloppenburg
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
| | - Taylor Marquis
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
| | - Laura Solomon
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
| | - Keara L McElroy-Yaggy
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
- Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA
| | - Jeffrey L Spees
- Department of Medicine, Stem Cell Core, University of Vermont, Colchester, VT 05446, USA
- Cardiovascular Research Institute, University of Vermont, Colchester, VT 05446, USA
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3
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Xu PC, Xuan M, Cheng B. Effects and mechanism of platelet-rich plasma on military drill injury: a review. Mil Med Res 2020; 7:56. [PMID: 33220706 PMCID: PMC7680596 DOI: 10.1186/s40779-020-00285-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2020] [Accepted: 11/04/2020] [Indexed: 02/07/2023] Open
Abstract
Military drill injury is a significant part of military medical research. The increase of training intensity and changes in training methods lead to differences in injury types. The ideal therapeutic modality should allow rapid healing at a reasonable cost and minimize impact on patients' life. Platelet -rich plasma (PRP), a platelet concentrate, is rich in a variety of growth factors and widely used clinically as a minimally invasive treatment. It plays an important role in injury repair and rehabilitation. In this article, we review the therapeutic role of PRP in military drill injury and its possible underlying mechanisms, with a focus on plantar fasciitis, stress fractures and other common injuries, in order to provide basic support for military reserve.
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Affiliation(s)
- Peng-Cheng Xu
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of Chinese PLA, No. 111 Liuhua Road, Yuexiu District, Guangzhou, 510010, Guangdong Province, China
| | - Min Xuan
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of Chinese PLA, No. 111 Liuhua Road, Yuexiu District, Guangzhou, 510010, Guangdong Province, China
| | - Biao Cheng
- Department of Burn and Plastic Surgery, General Hospital of Southern Theater Command of Chinese PLA, No. 111 Liuhua Road, Yuexiu District, Guangzhou, 510010, Guangdong Province, China.
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4
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Diosgenin and Its Fenugreek Based Biological Matrix Affect Insulin Resistance and Anabolic Hormones in a Rat Based Insulin Resistance Model. BIOMED RESEARCH INTERNATIONAL 2019; 2019:7213913. [PMID: 31080828 PMCID: PMC6475550 DOI: 10.1155/2019/7213913] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/07/2018] [Accepted: 03/21/2019] [Indexed: 01/02/2023]
Abstract
Fenugreek is known since ancient times as a traditional herbal medicine of its multiple beneficial effects. Fenugreek's most studied and employed effect is its hypoglycemic property, but it can also be useful for the treatment of certain thyroid disorders or for the treatment of anorexia. The regulation of glucose homeostasis is a complex mechanism, dependent on the interaction of different types of hormones and neurotransmitters or other compounds. For the study of how diosgenin and fenugreek seeds modify insulin sensitivity, we used a rat insulin resistance model induced by high-fat diet. Diosgenin in three different doses (1mg/bwkg, 10mg/bwkg, and 50 mg/bwkg, respectively) and fenugreek seed (0.2 g/bwkg) were administered orally for 6 weeks. Insulin sensitivity was determined by hyperinsulinemic euglycemic glucose clamp method. Our research group found that although glucose infusion rate was not significantly modified in either group, the increased insulin sensitivity index and high metabolic clearance rate of insulin found in the 1 mg/kg diosgenin and the fenugreek seed treated group suggested an improved peripheral insulin sensitivity. Results from the 10 mg/kg diosgenin group, however, suggest a marked insulin resistance. Fenugreek seed therapy results on the investigated anabolic hormones support the theory that, besides insulin and gastrointestinal peptides, the hypothalamic-hypopituitary axis regulated hormones synchronized action with IGF-1 also play an important role in the maintaining of normal glucose levels. Both diosgenin and fenugreek seeds are capable of interacting with substrates of the above-mentioned regulatory mechanisms, inducing serious hormonal disorders. Moreover, fenugreek seeds showed the ability to reduce the thyroid hormone levels at the periphery and to modify the T4/T3 ratio. It means that in healthy people this effect could be considered a severe side effect; however, in hypothyroidism this effect represents a possibility of alternative natural therapy.
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5
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Dai R, Hang Y, Liu Q, Zhang S, Wang L, Pan Y, Chen H. Improved neural differentiation of stem cells mediated by magnetic nanoparticle-based biophysical stimulation. J Mater Chem B 2019. [DOI: 10.1039/c9tb00678h] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/27/2023]
Abstract
Stem cell therapy shows great potential in the treatment of neurodegenerative diseases, in which efficient neural differentiation of stem cells is still challenging.
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Affiliation(s)
- Ran Dai
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials
- College of Chemistry
- Chemical Engineering and Materials Science
- Soochow University
- Suzhou
| | - Yingjie Hang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials
- College of Chemistry
- Chemical Engineering and Materials Science
- Soochow University
- Suzhou
| | - Qi Liu
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials
- College of Chemistry
- Chemical Engineering and Materials Science
- Soochow University
- Suzhou
| | - Sixuan Zhang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials
- College of Chemistry
- Chemical Engineering and Materials Science
- Soochow University
- Suzhou
| | - Lei Wang
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials
- College of Chemistry
- Chemical Engineering and Materials Science
- Soochow University
- Suzhou
| | - Yue Pan
- Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center
- Sun Yat-Sen Memorial Hospital
- Sun Yat-Sen University
- Guangzhou
- P. R. China
| | - Hong Chen
- State and Local Joint Engineering Laboratory for Novel Functional Polymeric Materials
- College of Chemistry
- Chemical Engineering and Materials Science
- Soochow University
- Suzhou
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6
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Guo X, Bai Y, Zhang L, Zhang B, Zagidullin N, Carvalho K, Du Z, Cai B. Cardiomyocyte differentiation of mesenchymal stem cells from bone marrow: new regulators and its implications. Stem Cell Res Ther 2018; 9:44. [PMID: 29482607 PMCID: PMC5828435 DOI: 10.1186/s13287-018-0773-9] [Citation(s) in RCA: 77] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
In the past years, cardiac mortality has decreased, but cardiac diseases are still responsible for millions of deaths every year worldwide. Bone-marrow mesenchymal stem cells (BMSCs) transplantation may be a promising therapeutic strategy because of its capacity to differentiate into cardiac cells. Current research indicates that chemical substances, microRNAs, and cytokines have biological functions that regulate the cardiomyocytes differentiation of BMSCs. In this review, we chiefly summarize the regulatory factors that induce BMSCs to differentiate into cardiomyocytes.
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Affiliation(s)
- Xiaofei Guo
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Yan Bai
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Li Zhang
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Bo Zhang
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Naufal Zagidullin
- Department of Internal Diseases, Bashkir State Medical University, Ufa, Russia
| | - Katherine Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pequeno Príncipe Faculty, Pelé Pequeno Príncipe Institute, Curitiba, Brazil
| | - Zhimin Du
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, Heilongjiang Province, 150081, People's Republic of China
| | - Benzhi Cai
- Department of Pharmacy, the Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Harbin, Heilongjiang Province, 150081, People's Republic of China.
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7
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Ku J, El-Hashash A. Stem Cell Roles and Applications in Genetic Neurodegenerative Diseases. STEM CELLS IN CLINICAL APPLICATIONS 2018. [DOI: 10.1007/978-3-319-98065-2_9] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
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8
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Gong H, Wang X, Wang L, Liu Y, Wang J, Lv Q, Pang H, Zhang Q, Wang Z. Inhibition of IGF-1 receptor kinase blocks the differentiation into cardiomyocyte-like cells of BMSCs induced by IGF-1. Mol Med Rep 2017; 16:787-793. [PMID: 28560388 PMCID: PMC5482190 DOI: 10.3892/mmr.2017.6639] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2016] [Accepted: 03/21/2017] [Indexed: 01/18/2023] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs) have the potential to transdifferentiate into cardiomyocyte-like cells (CLCs) if an appropriate cardiac environment is provided. Insulin-like growth factor-1 (IGF-1) plays an important role in the cell migration, survival and differentiation of BMSCs. However, the effect of IGF-1 on the cellular differentiation remains unclear. In the present study, BMSCs were isolated from rat femurs and tibias and the cells were purified at passage 6 (P6). IGF-1 and IGF-1 receptor (IGF-1R) kinase inhibitor I-OMe AG538 were added to detect if IGF-1 could induce BMSCs to transdifferentiate into CLCs and if I-OMe AG538 could inhibit IGF-1-mediated receptor activation and downstream signaling. Immunostaining demonstrated that all P6 BMSCs express CD29 and CD44 but not CD45. BMSCs induced by 15 ng/ml IGF-1 revealed positivity for cardiac troponin-T and cardiac troponin-I. The optimal induction time was 14 days but the expression of these proteins were incompletely inhibited by 300 nmol/l I-OMe AG538 and completely inhibited by 10 µmol/l I-OMe AG538. Western blotting showed that the level of IGF-1R autophosphorylation and the expression of cTnT and cTnI were higher when BMSCs were induced for 14 days. I-OMe AG538 selectively inhibited IGF-1-mediated growth and signal transduction and the inhibitory effect of I-OMe AG538 were not reverted in the presence of exogenous IGF-1. In addition, when a time course analysis of the effects of I-OMe AG538 on mitogen-activated protein kinase kinase and phosphatidylinositol 3-kinase signaling were done, we observed a transient inhibitory effect on Erk1/2 and Akt phosphorylation, in keeping with the inhibitory effects on cell growth. Taken together, these data indicate that I-OMe AG538 could inhibit IGF-1-induced CLCs in BMSCs and this effect is time- and concentration-dependent.
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Affiliation(s)
- Haibin Gong
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Xiuli Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Lei Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Ying Liu
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Jie Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Qian Lv
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Hui Pang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Qinglin Zhang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
| | - Zhenquan Wang
- Department of Cardiology, Xuzhou Central Hospital, Xuzhou Cardiovascular Disease Institute, Xuzhou, Jiangsu 221009, P.R. China
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9
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Der Sarkissian S, Lévesque T, Noiseux N. Optimizing stem cells for cardiac repair: Current status and new frontiers in regenerative cardiology. World J Stem Cells 2017; 9:9-25. [PMID: 28154736 PMCID: PMC5253186 DOI: 10.4252/wjsc.v9.i1.9] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2016] [Revised: 09/20/2016] [Accepted: 10/24/2016] [Indexed: 02/06/2023] Open
Abstract
Cell therapy has the potential to improve healing of ischemic heart, repopulate injured myocardium and restore cardiac function. The tremendous hope and potential of stem cell therapy is well understood, yet recent trials involving cell therapy for cardiovascular diseases have yielded mixed results with inconsistent data thereby readdressing controversies and unresolved questions regarding stem cell efficacy for ischemic cardiac disease treatment. These controversies are believed to arise by the lack of uniformity of the clinical trial methodologies, uncertainty regarding the underlying reparative mechanisms of stem cells, questions concerning the most appropriate cell population to use, the proper delivery method and timing in relation to the moment of infarction, as well as the poor stem cell survival and engraftment especially in a diseased microenvironment which is collectively acknowledged as a major hindrance to any form of cell therapy. Indeed, the microenvironment of the failing heart exhibits pathological hypoxic, oxidative and inflammatory stressors impairing the survival of transplanted cells. Therefore, in order to observe any significant therapeutic benefit there is a need to increase resilience of stem cells to death in the transplant microenvironment while preserving or better yet improving their reparative functionality. Although stem cell differentiation into cardiomyocytes has been observed in some instance, the prevailing reparative benefits are afforded through paracrine mechanisms that promote angiogenesis, cell survival, transdifferentiate host cells and modulate immune responses. Therefore, to maximize their reparative functionality, ex vivo manipulation of stem cells through physical, genetic and pharmacological means have shown promise to enable cells to thrive in the post-ischemic transplant microenvironment. In the present work, we will overview the current status of stem cell therapy for ischemic heart disease, discuss the most recurring cell populations employed, the mechanisms by which stem cells deliver a therapeutic benefit and strategies that have been used to optimize and increase survival and functionality of stem cells including ex vivo preconditioning with drugs and a novel “pharmaco-optimizer” as well as genetic modifications.
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10
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Wenzel K, Samal R, Hammer E, Dhople VM, Gross S, Völker U, Felix SB, Könemann S. Pathophysiological aldosterone levels modify the secretory activity of cardiac progenitor cells. Mol Cell Endocrinol 2017; 439:16-25. [PMID: 27742487 DOI: 10.1016/j.mce.2016.10.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2016] [Revised: 09/13/2016] [Accepted: 10/11/2016] [Indexed: 12/15/2022]
Abstract
Cardiac progenitor cells (CPCs) trigger regenerative processes via paracrine mechanisms in response to changes in their environment. In the present study we explored alterations in the secretory activity of CPCs induced by raised aldosterone levels symptomatic for heart failure. The cytokine profile of the supernatant of CPCs that were treated with the mineralocorticoid showed an induction of interleukin-6 secretion. Mass spectrometric analyses revealed an increase in the abundance of secreted proteins associated with regeneration and cell migration like gelsolin and galectin-1. Differential regulation of proteins associated with the extracellular matrix further points to an activation of cell migration. In response to supernatant, migration and proliferation were induced in CPCs, indicating a potential role of paracrine factors in the activation of CPCs from other regions of the heart or extra-cardiac sources. Changes in the secretory activity of CPCs might aim to compensate for the detrimental actions of aldosterone in heart failure.
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Affiliation(s)
- Kristin Wenzel
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
| | - Rasmita Samal
- Interfaculty Institute for Genetic and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
| | - Elke Hammer
- Interfaculty Institute for Genetic and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
| | - Vishnu M Dhople
- Interfaculty Institute for Genetic and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
| | - Stefan Gross
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
| | - Uwe Völker
- Interfaculty Institute for Genetic and Functional Genomics, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
| | - Stephan B Felix
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
| | - Stephanie Könemann
- Department of Internal Medicine B, University Medicine Greifswald, Greifswald, Germany; DZHK (German Centre for Cardiovascular Research), Partner Site Greifswald, Germany.
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11
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Xiang Q, Hong D, Liao Y, Cao Y, Liu M, Pang J, Zhou J, Wang G, Yang R, Wang M, Xiang AP. Overexpression of Gremlin1 in Mesenchymal Stem Cells Improves Hindlimb Ischemia in Mice by Enhancing Cell Survival. J Cell Physiol 2016; 232:996-1007. [PMID: 27579673 DOI: 10.1002/jcp.25578] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/21/2016] [Accepted: 08/29/2016] [Indexed: 01/04/2023]
Affiliation(s)
- Qiuling Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education; Sun Yat-sen University; Guangzhou Guangdong China
- Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou Guangdong China
| | - Dongxi Hong
- Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou Guangdong China
| | - Yan Liao
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education; Sun Yat-sen University; Guangzhou Guangdong China
| | - Yong Cao
- Cardiovascular Center; Gaozhou People's Hospital; Maoming Guangdong China
| | - Muyun Liu
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education; Sun Yat-sen University; Guangzhou Guangdong China
| | - Jun Pang
- Guizhou Provincial People's Hospital; Guizhou China
| | - Junjie Zhou
- Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou Guangdong China
| | - Guang Wang
- Division of Histology and Embryology; Medical College, Jinan University; Guangzhou China
| | - Renhao Yang
- Division of Histology and Embryology; Medical College, Jinan University; Guangzhou China
| | - Maosheng Wang
- Cardiovascular Center; Gaozhou People's Hospital; Maoming Guangdong China
| | - Andy Peng Xiang
- Center for Stem Cell Biology and Tissue Engineering, Key Laboratory for Stem Cells and Tissue Engineering, Ministry of Education; Sun Yat-sen University; Guangzhou Guangdong China
- Zhongshan School of Medicine; Sun Yat-sen University; Guangzhou Guangdong China
- Biotherapy Center, The Third Affiliated Hospital; Sun Yat-sen University; Guangzhou Guangdong China
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12
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Bao X, Lian X, Hacker TA, Schmuck EG, Qian T, Bhute VJ, Han T, Shi M, Drowley L, Plowright A, Wang QD, Goumans MJ, Palecek SP. Long-term self-renewing human epicardial cells generated from pluripotent stem cells under defined xeno-free conditions. Nat Biomed Eng 2016; 1. [PMID: 28462012 PMCID: PMC5408455 DOI: 10.1038/s41551-016-0003] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
The epicardium contributes both multi-lineage descendants and paracrine factors to the heart during cardiogenesis and cardiac repair, underscoring its potential for cardiac regenerative medicine. Yet little is known about the cellular and molecular mechanisms that regulate human epicardial development and regeneration. Here, we show that the temporal modulation of canonical Wnt signaling is sufficient for epicardial induction from 6 different human pluripotent stem cell (hPSC) lines, including a WT1-2A-eGFP knock-in reporter line, under chemically-defined, xeno-free conditions. We also show that treatment with transforming growth factor beta (TGF-β)-signalling inhibitors permitted long-term expansion of the hPSC-derived epicardial cells, resulting in a more than 25 population doublings of WT1+ cells in homogenous monolayers. The hPSC-derived epicardial cells were similar to primary epicardial cells both in vitro and in vivo, as determined by morphological and functional assays, including RNA-seq. Our findings have implications for the understanding of self-renewal mechanisms of the epicardium and for epicardial regeneration using cellular or small-molecule therapies.
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Affiliation(s)
- Xiaoping Bao
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA
| | - Xiaojun Lian
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA.,Departments of Biomedical Engineering, Biology and Huck Institutes of the Life Sciences, The Pennsylvania State University, University Park, PA 16802, USA
| | - Timothy A Hacker
- Department of Medicine, University of Wisconsin, Madison, WI 53706, USA
| | - Eric G Schmuck
- Department of Medicine, University of Wisconsin, Madison, WI 53706, USA
| | - Tongcheng Qian
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA
| | - Vijesh J Bhute
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA
| | - Tianxiao Han
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA
| | - Mengxuan Shi
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA
| | - Lauren Drowley
- Department of Cardiovascular and Metabolic Diseases Innovative Medicine Unit, AstraZeneca, Mölndal, 43183, Sweden
| | - Alleyn Plowright
- Department of Cardiovascular and Metabolic Diseases Innovative Medicine Unit, AstraZeneca, Mölndal, 43183, Sweden
| | - Qing-Dong Wang
- Department of Cardiovascular and Metabolic Diseases Innovative Medicine Unit, AstraZeneca, Mölndal, 43183, Sweden
| | - Marie-Jose Goumans
- Department of Molecular Cell Biology, Leiden University Medical Center, 2333 ZC Leiden, the Netherlands
| | - Sean P Palecek
- Department of Chemical & Biological Engineering, University of Wisconsin, Madison, WI 53706, USA
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13
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Wei W, Huang W, Yue J. Requirement of IP3 receptor 3 (IP3R3) in nitric oxide induced cardiomyocyte differentiation of mouse embryonic stem cells. Exp Cell Res 2016; 346:9-16. [PMID: 27349290 DOI: 10.1016/j.yexcr.2016.06.016] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2015] [Revised: 06/21/2016] [Accepted: 06/23/2016] [Indexed: 01/29/2023]
Abstract
Nitric oxide (NO) markedly induces cardiomyocyte (CM) differentiation of embryonic stem (ES) cells. Here we examined the role of the Ca(2+) signaling in the NO-induced CM differentiation of mouse ES cells. We found that NO induced intracellular Ca(2+) increases in ES cells in a dose-dependent manner, and application of IP3 pathway antagonists not only significantly inhibited this induced Ca(2+) increase but also abolished NO-induced CM differentiation of ES cells. Subsequently, all 3 types of inositol 1, 4, 5-trisphosphate (IP3) receptors (IP3Rs) in mouse ES cells were individually or triply knocked down. Interestingly, only knockdown of type 3 IP3R (IP3R3) or triple-knockdown of three types of IP3Rs significantly inhibited the NO-induced Ca(2+) increases. Consistently, IP3R3 knockdown blocked the NO-induced CM differentiation of ES cells. CMs derived from IP3R3 knockdown ES cells also showed both structural and functional defects. In summary, our results indicate that the IP3R3-Ca(2+) pathway is required for NO-induced CM differentiation of ES cells.
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Affiliation(s)
- Wenjie Wei
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China; Department of Biology, South University of Science and Technology of China, Shenzhen 518052, China
| | - Wei Huang
- Department of Biology, South University of Science and Technology of China, Shenzhen 518052, China
| | - Jianbo Yue
- Department of Biomedical Sciences, City University of Hong Kong, Hong Kong, China.
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14
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Rojas SV, Meier M, Zweigerdt R, Eckardt D, Rathert C, Schecker N, Schmitto JD, Rojas-Hernandez S, Martin U, Kutschka I, Haverich A, Martens A. Multimodal Imaging for In Vivo Evaluation of Induced Pluripotent Stem Cells in a Murine Model of Heart Failure. Artif Organs 2016; 41:192-199. [DOI: 10.1111/aor.12728] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 01/18/2016] [Accepted: 01/19/2016] [Indexed: 12/23/2022]
Affiliation(s)
- Sebastian V. Rojas
- Department of Cardiothoracic; Transplantation and Vascular Surgery, Hannover Medical School
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
| | - Martin Meier
- Central Animal Laboratory; Hannover Medical School; Hannover
| | - Robert Zweigerdt
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
| | | | - Christian Rathert
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
| | - Natalie Schecker
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
| | - Jan D. Schmitto
- Department of Cardiothoracic; Transplantation and Vascular Surgery, Hannover Medical School
| | - Sara Rojas-Hernandez
- Department of Anaesthesiology and Intensive Care Medicine; Hannover Medical School; Hannover Germany
| | - Ulrich Martin
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
| | - Ingo Kutschka
- Department of Cardiothoracic; Transplantation and Vascular Surgery, Hannover Medical School
| | - Axel Haverich
- Department of Cardiothoracic; Transplantation and Vascular Surgery, Hannover Medical School
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
| | - Andreas Martens
- Department of Cardiothoracic; Transplantation and Vascular Surgery, Hannover Medical School
- Leibniz Research Laboratories for Biotechnology and Artificial Organs-REBIRTH-Cluster of Excellence; Hannover Medical School
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15
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Vasam G, Joshi S, Jarajapu YPR. Impaired Mobilization of Vascular Reparative Bone Marrow Cells in Streptozotocin-Induced Diabetes but not in Leptin Receptor-Deficient db/db Mice. Sci Rep 2016; 6:26131. [PMID: 27188595 PMCID: PMC4870646 DOI: 10.1038/srep26131] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2016] [Accepted: 04/27/2016] [Indexed: 01/10/2023] Open
Abstract
Diabetes is associated with impaired mobilization of bone marrow stem/progenitor cells that accelerate vascularization of ischemic areas. This study characterized mobilization of vascular reparative bone marrow progenitor cells in mouse models of diabetes. Age-matched control or streptozotocin (STZ)-induced diabetic, and db/db mice with lean-controls were studied. Mobilization induced by G-CSF, AMD3100 or ischemia was evaluated by flow cytometric enumeration of circulating Lin(-)Sca-1(+)cKit(+) (LSK) cells, and by colony forming unit (CFU) assay. The circulating WBCs and LSKs, and CFUs were reduced in both models with a shorter duration (10-12 weeks) of diabetes compared to their respective controls. Longer duration of STZ-diabetes (≥20 weeks) induced impairment of G-CSF- or AMD3100-mobilization (P < 0.01, n = 8). In db/db mice, mobilization by G-CSF or AMD3100 was either increased or unaffected (P < 0.05, n = 6 to 8). Proliferation, migration, and ischemia-induced mobilization, of LSK cells were impaired in both models. Leptin receptor antagonist, PESLAN-1, increased G-CSF- or AMD3100-mobilization of WBCs and LSKs, compared to the untreated. Leptin increased basal WBCs, decreased basal and AMD3100-mobilized LSK cells, and had no effect on G-CSF. These results suggest that mobilopathy is apparent in STZ-diabetes but not in db/db mice. Leptin receptor antagonism would be a promising approach for reversing diabetic bone marrow mobilopathy.
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Affiliation(s)
- Goutham Vasam
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA
| | - Shrinidh Joshi
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA
| | - Yagna P. R. Jarajapu
- Department of Pharmaceutical Sciences, North Dakota State University, Fargo, North Dakota, USA
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16
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Abdelwahid E, Kalvelyte A, Stulpinas A, de Carvalho KAT, Guarita-Souza LC, Foldes G. Stem cell death and survival in heart regeneration and repair. Apoptosis 2016; 21:252-68. [PMID: 26687129 PMCID: PMC5200890 DOI: 10.1007/s10495-015-1203-4] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cardiovascular diseases are major causes of mortality and morbidity. Cardiomyocyte apoptosis disrupts cardiac function and leads to cardiac decompensation and terminal heart failure. Delineating the regulatory signaling pathways that orchestrate cell survival in the heart has significant therapeutic implications. Cardiac tissue has limited capacity to regenerate and repair. Stem cell therapy is a successful approach for repairing and regenerating ischemic cardiac tissue; however, transplanted cells display very high death percentage, a problem that affects success of tissue regeneration. Stem cells display multipotency or pluripotency and undergo self-renewal, however these events are negatively influenced by upregulation of cell death machinery that induces the significant decrease in survival and differentiation signals upon cardiovascular injury. While efforts to identify cell types and molecular pathways that promote cardiac tissue regeneration have been productive, studies that focus on blocking the extensive cell death after transplantation are limited. The control of cell death includes multiple networks rather than one crucial pathway, which underlies the challenge of identifying the interaction between various cellular and biochemical components. This review is aimed at exploiting the molecular mechanisms by which stem cells resist death signals to develop into mature and healthy cardiac cells. Specifically, we focus on a number of factors that control death and survival of stem cells upon transplantation and ultimately affect cardiac regeneration. We also discuss potential survival enhancing strategies and how they could be meaningful in the design of targeted therapies that improve cardiac function.
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Affiliation(s)
- Eltyeb Abdelwahid
- Feinberg School of Medicine, Feinberg Cardiovascular Research Institute, Northwestern University, 303 E. Chicago Ave., Tarry 14-725, Chicago, IL, 60611, USA.
| | - Audrone Kalvelyte
- Department of Molecular Cell Biology, Vilnius University Institute of Biochemistry, Vilnius, Lithuania
| | - Aurimas Stulpinas
- Department of Molecular Cell Biology, Vilnius University Institute of Biochemistry, Vilnius, Lithuania
| | - Katherine Athayde Teixeira de Carvalho
- Cell Therapy and Biotechnology in Regenerative Medicine Research Group, Pequeno Príncipe Faculty, Pelé Pequeno Príncipe Institute, Curitiba, Paraná, 80250-200, Brazil
| | - Luiz Cesar Guarita-Souza
- Experimental Laboratory of Institute of Biological and Health Sciences of Pontifical Catholic University of Parana, Curitiba, Paraná, 80215-901, Brazil
| | - Gabor Foldes
- National Heart and Lung Institute, Imperial College London, Imperial Centre for Experimental and Translational Medicine, Du Cane Road, London, W12 0NN, UK
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17
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Improving Cell Engraftment in Cardiac Stem Cell Therapy. Stem Cells Int 2015; 2016:7168797. [PMID: 26783405 PMCID: PMC4691492 DOI: 10.1155/2016/7168797] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2015] [Revised: 07/22/2015] [Accepted: 08/11/2015] [Indexed: 12/18/2022] Open
Abstract
Myocardial infarction (MI) affects millions of people worldwide. MI causes massive cardiac cell death and heart function decrease. However, heart tissue cannot effectively regenerate by itself. While stem cell therapy has been considered an effective approach for regeneration, the efficacy of cardiac stem cell therapy remains low due to inferior cell engraftment in the infarcted region. This is mainly a result of low cell retention in the tissue and poor cell survival under ischemic, immune rejection and inflammatory conditions. Various approaches have been explored to improve cell engraftment: increase of cell retention using biomaterials as cell carriers; augmentation of cell survival under ischemic conditions by preconditioning cells, genetic modification of cells, and controlled release of growth factors and oxygen; and enhancement of cell survival by protecting cells from excessive inflammation and immune surveillance. In this paper, we review current progress, advantages, disadvantages, and potential solutions of these approaches.
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18
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Bilgimol JC, Ragupathi S, Vengadassalapathy L, Senthil NS, Selvakumar K, Ganesan M, Manjunath SR. Stem cells: An eventual treatment option for heart diseases. World J Stem Cells 2015; 7:1118-1126. [PMID: 26435771 PMCID: PMC4591785 DOI: 10.4252/wjsc.v7.i8.1118] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/18/2015] [Revised: 07/04/2015] [Accepted: 08/03/2015] [Indexed: 02/06/2023] Open
Abstract
Stem cells are of global excitement for various diseases including heart diseases. It is worth to understand the mechanism or role of stem cells in the treatment of heart failure. Bone marrow derived stem cells are commonly practiced with an aim to improve the function of the heart. The majority of studies have been conducted with acute myocardial infarction and a few has been investigated with the use of stem cells for treating chronic or dilated cardiomyopathy. Heterogeneity in the treated group using stem cells has greatly emerged. Ever increasing demand for any alternative made is of at most priority for cardiomyopathy. Stem cells are of top priority with the current impact that has generated among physicians. However, meticulous selection of proper source is required since redundancy is clearly evident with the present survey. This review focuses on the methods adopted using stem cells for heart diseases and outcomes that are generated so far with an idea to determine the best therapeutic possibility in order to fulfill the present demand.
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19
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Li J, Zhu K, Yang S, Wang Y, Guo C, Yin K, Wang C, Lai H. Fibrin patch-based insulin-like growth factor-1 gene-modified stem cell transplantation repairs ischemic myocardium. Exp Biol Med (Maywood) 2015; 240:585-92. [PMID: 25767192 DOI: 10.1177/1535370214556946] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2014] [Accepted: 09/08/2014] [Indexed: 02/03/2023] Open
Abstract
Bone marrow mesenchymal stem cells (BMSCs), tissue-engineered cardiac patch, and therapeutic gene have all been proposed as promising therapy strategies for cardiac repair after myocardial infarction. In our study, BMSCs were modified with insulin-like growth factor-1 (IGF-1) gene, loaded into a fibrin patch, and then transplanted into a porcine model of ischemia/reperfusion (I/R) myocardium injury. The results demonstrated that IGF-1 gene overexpression could promote proliferation of endothelial cells and cardiomyocyte-like differentiation of BMSCs in vitro. Four weeks after transplantation of fibrin patch loaded with gene-modified BMSCs, IGF-1 overexpression could successfully promote angiogenesis, inhibit remodeling, increase grafted cell survival and reduce apoptosis. In conclusion, the integrated strategy, which combined fibrin patch with IGF-1 gene modified BMSCs, could promote the histological cardiac repair for a clinically relevant porcine model of I/R myocardium injury.
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Affiliation(s)
- Jun Li
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
| | - Kai Zhu
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
| | - Shan Yang
- Department of Radiology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China
| | - Yulin Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
| | - Changfa Guo
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
| | - Kanhua Yin
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
| | - Chunsheng Wang
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
| | - Hao Lai
- Department of Cardiac Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China Shanghai Institute of Cardiovascular Disease, Shanghai 200032, P.R. China
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20
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Antanavičiūtė I, Ereminienė E, Vysockas V, Račkauskas M, Skipskis V, Rysevaitė K, Treinys R, Benetis R, Jurevičius J, Skeberdis VA. Exogenous connexin43-expressing autologous skeletal myoblasts ameliorate mechanical function and electrical activity of the rabbit heart after experimental infarction. Int J Exp Pathol 2014; 96:42-53. [PMID: 25529770 DOI: 10.1111/iep.12109] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/05/2014] [Accepted: 10/26/2014] [Indexed: 12/19/2022] Open
Abstract
Acute myocardial infarction is one of the major causes of mortality worldwide. For regeneration of the rabbit heart after experimentally induced infarction we used autologous skeletal myoblasts (SMs) due to their high proliferative potential, resistance to ischaemia and absence of immunological and ethical concerns. The cells were characterized with muscle-specific and myogenic markers. Cell transplantation was performed by injection of cell suspension (0.5 ml) containing approximately 6 million myoblasts into the infarction zone. The animals were divided into four groups: (i) no injection; (ii) sham injected; (iii) injected with wild-type SMs; and (iv) injected with SMs expressing connexin43 fused with green fluorescent protein (Cx43EGFP). Left ventricular ejection fraction (LVEF) was evaluated by 2D echocardiography in vivo before infarction, when myocardium has stabilized after infarction, and 3 months after infarction. Electrical activity in the healthy and infarction zones of the heart was examined ex vivo in Langendorff-perfused hearts by optical mapping using di-4-ANEPPS, a potential sensitive fluorescent dye. We demonstrate that SMs in the coculture can couple electrically not only to abutted but also to remote acutely isolated allogenic cardiac myocytes through membranous tunnelling tubes. The beneficial effect of cellular therapy on LVEF and electrical activity was observed in the group of animals injected with Cx43EGFP-expressing SMs. L-type Ca(2+) current amplitude was approximately fivefold smaller in the isolated SMs compared to healthy myocytes suggesting that limited recovery of LVEF may be related to inadequate expression or function of L-type Ca(2+) channels in transplanted differentiating SMs.
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Affiliation(s)
- Ieva Antanavičiūtė
- Institute of Cardiology, Medical Academy, Lithuanian University of Health Sciences, Kaunas, Lithuania
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21
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Iso Y, Rao KS, Poole CN, Zaman AKMT, Curril I, Sobel BE, Kajstura J, Anversa P, Spees JL. Priming with ligands secreted by human stromal progenitor cells promotes grafts of cardiac stem/progenitor cells after myocardial infarction. Stem Cells 2014; 32:674-83. [PMID: 24022988 DOI: 10.1002/stem.1546] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2013] [Revised: 03/10/2013] [Accepted: 08/13/2013] [Indexed: 01/01/2023]
Abstract
Transplantation of culture-expanded adult stem/progenitor cells often results in poor cellular engraftment, survival, and migration into sites of tissue injury. Mesenchymal cells including fibroblasts and stromal cells secrete factors that protect injured tissues, promote tissue repair, and support many types of stem/progenitor cells in culture. We hypothesized that secreted factors in conditioned medium (CdM) from adult bone marrow-derived multipotent stromal cells (MSCs) could be used to prime adult cardiac stem/progenitor cells (CSCs/CPCs) and improve graft success after myocardial infarction (MI). Incubation of adult rat CPCs in CdM from human MSCs isolated by plastic adherence or by magnetic sorting against CD271 (a.k.a., p75 low-affinity nerve growth factor receptor; p75MSCs) induced phosphorylation of STAT3 and Akt in CPCs, supporting their proliferation under normoxic conditions and survival under hypoxic conditions (1% oxygen). Priming CSCs with 30× p75MSC CdM for 30 minutes prior to transplantation into subepicardial tissue 1 day after MI markedly increased engraftment compared with vehicle priming. Screening CdM with neutralizing/blocking antibodies identified connective tissue growth factor (CTGF) and Insulin as key factors in p75MSC CdM that protected CPCs. Human CTGF peptide (CTGF-D4) and Insulin synergistically promoted CPC survival during hypoxia in culture. Similar to CdM priming, priming of CSCs with CTGF-D4 and Insulin for 30 minutes prior to transplantation promoted robust engraftment, survival, and migration of CSC derivatives at 1 week and 1 month after MI. Our results indicate that short-term priming of human CSCs with CTGF-D4 and Insulin may improve graft success and cardiac regeneration in patients with MI.
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Affiliation(s)
- Yoshitaka Iso
- Department of Medicine, Stem Cell Core and, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA; Department of Medicine, Cardiovascular Research Institute, University of Vermont, Colchester, Vermont, USA
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22
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Hyperthermia differently affects connexin43 expression and gap junction permeability in skeletal myoblasts and HeLa cells. Mediators Inflamm 2014; 2014:748290. [PMID: 25143668 PMCID: PMC4131114 DOI: 10.1155/2014/748290] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2014] [Revised: 05/30/2014] [Accepted: 06/02/2014] [Indexed: 12/11/2022] Open
Abstract
Stress kinases can be activated by hyperthermia and modify the expression level and properties of membranous and intercellular channels. We examined the role of c-Jun NH2-terminal kinase (JNK) in hyperthermia-induced changes of connexin43 (Cx43) expression and permeability of Cx43 gap junctions (GJs) in the rabbit skeletal myoblasts (SkMs) and Cx43-EGFP transfected HeLa cells. Hyperthermia (42°C for 6 h) enhanced the activity of JNK and its target, the transcription factor c-Jun, in both SkMs and HeLa cells. In SkMs, hyperthermia caused a 3.2-fold increase in the total Cx43 protein level and enhanced the efficacy of GJ intercellular communication (GJIC). In striking contrast, hyperthermia reduced the total amount of Cx43 protein, the number of Cx43 channels in GJ plaques, the density of hemichannels in the cell membranes, and the efficiency of GJIC in HeLa cells. Both in SkMs and HeLa cells, these changes could be prevented by XG-102, a JNK inhibitor. In HeLa cells, the changes in Cx43 expression and GJIC under hyperthermic conditions were accompanied by JNK-dependent disorganization of actin cytoskeleton stress fibers while in SkMs, the actin cytoskeleton remained intact. These findings provide an attractive model to identify the regulatory players within signalosomes, which determine the cell-dependent outcomes of hyperthermia.
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23
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Li N, Pasha Z, Ashraf M. Reversal of ischemic cardiomyopathy with Sca-1+ stem cells modified with multiple growth factors. PLoS One 2014; 9:e93645. [PMID: 24705272 PMCID: PMC3976296 DOI: 10.1371/journal.pone.0093645] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2013] [Accepted: 03/09/2014] [Indexed: 01/09/2023] Open
Abstract
Background We hypothesized that bone marrow derived Sca-1+ stem cells (BM Sca-1+) transduced with multiple therapeutic cytokines with diverse effects will induce faster angiomyogenic differentiation in the infarcted myocardium. Methods and Results BM Sca-1+ were purified from transgenic male mice expressing GFP. Plasmids encoding for select quartet of growth factors, i.e., human IGF-1, VEGF, SDF-1α and HGF were prepared and used for genetic modification of Sca-1+ cells (GFSca-1+). Scramble transfected cells (ScSca-1+) were used as a control. RT-PCR and western blotting showed significantly higher expression of the growth factors in GFSca-1+. Besides the quartet of the therapeutic growth factors, PCR based growth factor array showed upregulation of multiple angiogenic and prosurvival factors such as Ang-1, Ang-2, MMP9, Cx43, BMP2, BMP5, FGF2, and NGF in GFSca-1+ (p<0.01 vsScSca-1+). LDH and TUNEL assays showed enhanced survival of GFSca-1+ under lethal anoxia (p<0.01 vs ScSca-1+). MTS assay showed significant increased cell proliferation in GFSca-1+ (p<0.05 vsScSca-1+). For in vivo study, female mice were grouped to receive the intramyocardial injection of 15 μl DMEM without cells (group-1) or containing 2.5×105ScSca-1+ (group-2) or GFSca-1+ (group-3) immediately after coronary artery ligation. As indicated by Sry gene, a higher survival of GFSca-1+ in group-3 on day4 (2.3 fold higher vs group-2) was observed with massive mobilization of stem and progenitor cells (cKit+, Mdr1+, Cxcr4+ cells). Heart tissue sections immunostained for actinin and Cx43 at 4 weeks post engraftment showed extensive myofiber formation and expression of gap junctions. Immunostaining for vWF showed increased blood vessel density in both peri-infarct and infarct regions in group-3. Infarct size was attenuated and the global heart function was improved in group-3 as compared to group-2. Conclusions Administration of BM Sca-1+ transduced with multiple genes is a novel approach to treat infarcted heart for its regeneration.
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Affiliation(s)
- Ning Li
- Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio, United States of America
| | - Zeeshan Pasha
- Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America
| | - Muhammad Ashraf
- Department of Pharmacology, University of Illinois at Chicago, Chicago, Illinois, United States of America
- * E-mail:
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24
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Vassilakos G, Philippou A, Tsakiroglou P, Koutsilieris M. Biological activity of the e domain of the IGF-1Ec as addressed by synthetic peptides. Hormones (Athens) 2014; 13:182-96. [PMID: 24776619 DOI: 10.1007/bf03401333] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) is a multipotent growth factor involved in the growth, development and regulation of homeostasis in a tissue-specific manner. Alternative splicing, multiple transcription initiation sites and different polyadelynation signals give rise to diverse mRNA isoforms, such as IGF-1Ea, IGF-1Eb and IGF-1Ec transcripts. There is increasing interest in the expression of the IGF-1 isoforms and their potential distinct biological role. IGF-1Ec results from alternative splicing of exons 4-5-6 and its expression is upregulated in various conditions and pathologies. Recent studies have shown that IGF-1Ec is preferentially increased after injury in skeletal muscle during post-infarctal myocardium remodelling and in cancer tissues and cell lines. A synthetic analogue corresponding to the last 24 aa of the E domain of the IGF-1Ec isoform has been used to elucidate its potential biological role. The aim of the present review is to describe and discuss the putative bioactivity of the E domain of the IGF-1Ec isoform.
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Affiliation(s)
- George Vassilakos
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Anastassios Philippou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Tsakiroglou
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Michael Koutsilieris
- Department of Experimental Physiology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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25
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Johnson AM, Kartha CC. Proliferation of murine c-kit(pos) cardiac stem cells stimulated with IGF-1 is associated with Akt-1 mediated phosphorylation and nuclear export of FoxO3a and its effect on downstream cell cycle regulators. Growth Factors 2014; 32:53-62. [PMID: 24580070 DOI: 10.3109/08977194.2014.889694] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Insulin-like growth factor-1 (IGF-1) is known to promote proliferation in many cell types including c-kit(pos) cardiac stem cells (CSCs). Downstream signaling pathways of IGF-1 induced CSC proliferation have not been investigated. An important downstream target of IGF-1/Akt-1 signaling is FoxO3a, a key negative regulator of cell-cycle progression. We studied the effect of IGF-1 on proliferation of c-kit(pos) murine CSCs and found that IGF-1-mediated cell proliferation is associated with FoxO3a phosphorylation and inactivation of its transcriptional activity. PI3 inhibitors LY294002 and Wortmannin abolished the effect of IGF-1 on FoxO3a phosphorylation indicating that FoxO3a phosphorylation is mediated by PI3/Akt-1 pathway. In cells with FoxO3a translocation to the cytoplasm, there is decreased expression of cell-cycle inhibitors such as p27(kip1) and p57(kip2) and increased expression of CyclinD1. Our study provides evidence that IGF-1 induced CSC proliferation could be the result of FoxO3a inactivation and its downstream effect on cell-cycle regulators.
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Affiliation(s)
- Ann Mary Johnson
- Cardiovascular Disease Biology Division, Rajiv Gandhi Centre for Biotechnology , Trivandrum, Kerala , India
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26
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Pourrajab F, Babaei Zarch M, Baghi Yazdi M, Rahimi Zarchi A, Vakili Zarch A. Application of stem cell/growth factor system, as a multimodal therapy approach in regenerative medicine to improve cell therapy yields. Int J Cardiol 2014; 173:12-9. [PMID: 24612559 DOI: 10.1016/j.ijcard.2014.02.006] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/02/2013] [Revised: 12/26/2013] [Accepted: 02/08/2014] [Indexed: 12/13/2022]
Abstract
Stem cells hold a great promise for regenerative medicine, especially for replacing cells in infarcted organ that hardly have any intrinsic renewal capacity, including heart and brain. Signaling pathways that regulate pluripotency or lineage-specific gene and protein expression have been the major focus of stem cell research. Between them, there are some well known signaling pathways such as GF/GFR systems, SDF-1α/CXC4 ligand receptor interaction and PI3K/Akt signaling, and cytokines may regulate cell fate decisions, and can be utilized to positively influence cell therapy outcomes or accentuate synergistic compliance. For example, contributing factors in the progression of heart failure are both the loss of cardiomyocytes after myocardial infarction, and the absence of an adequate endogenous repair signaling. Combining cell engraftment with therapeutic signaling factor delivery is more exciting in terms of host progenitor/donor stem cell survival and proliferation. Thus stem cell-based therapy, besides triggering signaling pathways through GF/GFR systems can become a realistic option in regenerative processes for replacing lost cells and reconstituting the damaged organ, as before.
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Affiliation(s)
- Fatemeh Pourrajab
- School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran; Department of Clinical Biochemistry and Molecular Biology, School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran.
| | | | | | - Abolfazl Rahimi Zarchi
- School of Nursing, University of Social Welfare and Rehabilitation Sciences, Tehran, Iran
| | - Abbas Vakili Zarch
- School of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
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27
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28
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Peng Y, Huang S, Wu Y, Cheng B, Nie X, Liu H, Ma K, Zhou J, Gao D, Feng C, Yang S, Fu X. Platelet rich plasma clot releasate preconditioning induced PI3K/AKT/NFκB signaling enhances survival and regenerative function of rat bone marrow mesenchymal stem cells in hostile microenvironments. Stem Cells Dev 2013; 22:3236-51. [PMID: 23885779 PMCID: PMC3868358 DOI: 10.1089/scd.2013.0064] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2013] [Accepted: 07/25/2013] [Indexed: 01/07/2023] Open
Abstract
Mesenchymal stem cells (MSCs) have been optimal targets in the development of cell based therapies, but their limited availability and high death rate after transplantation remains a concern in clinical applications. This study describes novel effects of platelet rich clot releasate (PRCR) on rat bone marrow-derived MSCs (BM-MSCs), with the former driving a gene program, which can reduce apoptosis and promote the regenerative function of the latter in hostile microenvironments through enhancement of paracrine/autocrine factors. By using reverse transcription-polymerase chain reaction, immunofluorescence and western blot analyses, we showed that PRCR preconditioning could alleviate the apoptosis of BM-MSCs under stress conditions induced by hydrogen peroxide (H2O2) and serum deprivation by enhancing expression of vascular endothelial growth factor and platelet-derived growth factor (PDGF) via stimulation of the platelet-derived growth factor receptor (PDGFR)/PI3K/AKT/NF-κB signaling pathways. Furthermore, the effects of PRCR preconditioned GFP-BM-MSCs subcutaneously transplanted into rats 6 h after wound surgery were examined by histological and other tests from days 0-22 after transplantation. Engraftment of the PRCR preconditioned BM-MSCs not only significantly attenuated apoptosis and wound size but also improved epithelization and blood vessel regeneration of skin via regulation of the wound microenvironment. Thus, preconditioning with PRCR, which reprograms BM-MSCs to tolerate hostile microenvironments and enhance regenerative function by increasing levels of paracrine factors through PDGFR-α/PI3K/AKT/NF-κB signaling pathways would be a safe method for boosting the effectiveness of transplantation therapy in the clinic.
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Affiliation(s)
- Yan Peng
- The Key Laboratory of Trauma Treatment & Tissue Repair of Tropical Area, PLA, Department of Plastic Surgery, Guangzhou General Hospital of Guangzhou Command, Guangzhou, People's Republic of China
- Southern Medical University, Guangzhou, People's Republic of China
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Sha Huang
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, People's Republic of China
| | - Yan Wu
- Heilongjiang Key Laboratory of Anti-Fibrosis Biotherapy, Mudanjiang Medical College, Mudanjiang, People's Republic of China
| | - Biao Cheng
- The Key Laboratory of Trauma Treatment & Tissue Repair of Tropical Area, PLA, Department of Plastic Surgery, Guangzhou General Hospital of Guangzhou Command, Guangzhou, People's Republic of China
| | - Xiaohu Nie
- Southern Medical University, Guangzhou, People's Republic of China
| | - Hongwei Liu
- Key Laboratory for Regenerative Medicine, Ministry of Education, Department of Plastic Surgery, The First Affiliated Hospital of Jinan University, Guangzhou, People's Republic of China
| | - Kui Ma
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Jiping Zhou
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Dongyun Gao
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Changjiang Feng
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Siming Yang
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
| | - Xiaobing Fu
- Burns Institute, Trauma Center of Postgraduate Medical College, The First Affiliated Hospital, General Hospital of PLA, Beijing, People's Republic of China
- Wound Healing and Cell Biology Laboratory, Institute of Basic Medical Sciences, General Hospital of PLA, Beijing, People's Republic of China
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29
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Mao J, Lv Z, Zhuang Y. MicroRNA-23a is involved in tumor necrosis factor-α induced apoptosis in mesenchymal stem cells and myocardial infarction. Exp Mol Pathol 2013; 97:23-30. [PMID: 24269648 DOI: 10.1016/j.yexmp.2013.11.005] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2012] [Revised: 11/01/2013] [Accepted: 11/12/2013] [Indexed: 01/16/2023]
Abstract
Cell therapy has emerged as an attractive therapeutic modality to treat myocardial infarction (MI) via repairing damaged myocardium, and mesenchymal stem cells (MSCs) are an appealing therapeutic approach for cardiac regeneration. However, the clinical application of MSC-based therapy is restricted because of the poor survival of implanted cells, and this poor survival remains poorly understood. Using a tumor necrosis factor (TNF)-α-induced bone marrow (BM)-MSC injury model in vitro and a rat MI model in vivo, we showed in the current study that miR-23a was involved in TNF-α-induced BM-MSC apoptosis through regulating caspase-7 and that the injection of BM-MSCs overexpressing miR-23a could improve left ventricular (LV) function and reduce infarct size in the rat MI model. Our findings elucidate the etiology of MI and provide an alternative treatment strategy for patients with heart failure caused by MI who are not optimal candidates for surgical treatment.
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Affiliation(s)
- Jianqiang Mao
- Department of Cardiovascular Surgery, Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai China; Department of Cardiovascular Surgery, Shanghai First People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai China
| | - Zhiqian Lv
- Department of Cardiovascular Surgery, Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai China.
| | - Yu Zhuang
- Department of Cardiovascular Surgery, Sixth People's Hospital, Shanghai Jiaotong University School of Medicine, Shanghai China
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30
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Jin E, Kim JM, Kim SW. Priming of mononuclear cells with a combination of growth factors enhances wound healing via high angiogenic and engraftment capabilities. J Cell Mol Med 2013; 17:1644-51. [PMID: 24118840 PMCID: PMC3914645 DOI: 10.1111/jcmm.12152] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2013] [Accepted: 09/04/2013] [Indexed: 12/26/2022] Open
Abstract
Recently, we demonstrated that a specific combination of growth factors enhances the survival, adhesion and angiogenic potential of mononuclear cells (MNCs). In this study, we sought to investigate the changes of the angiogenic potential of MNCs after short-time priming with a specific combination of growth factors. MNCs were isolated using density gradient centrifugation and incubated with a priming cocktail containing epidermal growth factor (EGF), insulin-like growth factor (IGF)-1, fibroblast growth factor (FGF)-2, FMS-like tyrosine kinase (Flt)-3L, Angiopoietin (Ang)-1, granulocyte chemotactic protein (GCP)-2 and thrombopoietin (TPO) (all 400 ng/ml) for 15, 30 and 60 min. Wounds in nonobese diabetic-severe combined immune deficiency (NOD-SCID) mice were created by skin excision followed by cell transplantation. We performed a qRT-PCR analysis on the growth factor–primed cells. The angiogenic factors vascular endothelial growth factor (VEGF)-A, FGF-2, hepatocyte growth factor (HGF), platelet-derived growth factor (PDGF) and interleukin (IL)-8 and the anti-apoptotic factors IGF-1 and transforming growth factor-β1 were significantly elevated in the MNCs primed for 30 min. (T30) compared with the non-primed MNCs (T0). The scratch wound assay revealed that T30- conditioned media (CM) significantly increased the rate of fibroblast-mediated wound closure compared with the rates from T0-CM and human umbilical vein endothelial cells (HUVEC)-CM at 20 hrs. In vivo wound healing results revealed that the T30-treated wounds demonstrated accelerated wound healing at days 7 and 14 compared with those treated with T0. The histological analyses demonstrated that the number of engrafted cells and transdifferentiated keratinocytes in the wounds were significantly higher in the T30-transplanted group than in the T0-transplanted group. In conclusion, this study suggests that short-term priming of MNCs with growth factors might be alternative therapeutic option for cell-based therapies.
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Affiliation(s)
- Enze Jin
- Department of Cardiology, The Fourth Affiliated Hospital of Harbin Medical University, Harbin, China
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31
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Moon SH, Kang SW, Park SJ, Bae D, Kim SJ, Lee HA, Kim KS, Hong KS, Kim JS, Do JT, Byun KH, Chung HM. The use of aggregates of purified cardiomyocytes derived from human ESCs for functional engraftment after myocardial infarction. Biomaterials 2013; 34:4013-4026. [DOI: 10.1016/j.biomaterials.2013.02.022] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2013] [Accepted: 02/10/2013] [Indexed: 11/15/2022]
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32
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Xue P, Wu X, Zhou L, Ma H, Wang Y, Liu Y, Ma J, Li Y. IGF1 promotes osteogenic differentiation of mesenchymal stem cells derived from rat bone marrow by increasing TAZ expression. Biochem Biophys Res Commun 2013; 433:226-31. [DOI: 10.1016/j.bbrc.2013.02.088] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2013] [Accepted: 02/23/2013] [Indexed: 01/10/2023]
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33
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Embryonic stem (ES) cell-derived cardiomyocytes: A good candidate for cell therapy applications. Cell Biol Int 2013; 33:325-36. [DOI: 10.1016/j.cellbi.2008.12.001] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2008] [Revised: 10/24/2008] [Accepted: 12/05/2008] [Indexed: 01/31/2023]
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34
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Z. Asumda F. Towards the development of a reliable protocol for mesenchymal stem cell cardiomyogenesis. ACTA ACUST UNITED AC 2013. [DOI: 10.4236/scd.2013.31003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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35
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Puri G, Kumar K, Singh R, Singh RK, Yasotha T, Ranjan R, Kumar M, Das BC, Singh G, Sarkar M, Bag S. Effects of Growth Factors on Establishment and Propagation of Embryonic Stem Cells from Very Early Stage IVF Embryos and Their Characterization in Buffalo. Int J Stem Cells 2012; 5:96-103. [PMID: 24298362 PMCID: PMC3840990 DOI: 10.15283/ijsc.2012.5.2.96] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/09/2012] [Indexed: 11/09/2022] Open
Abstract
BACKGROUND AND OBJECTIVES Although ES cells have been derived from very early stage embryos in different species, but, so far ES cell line could be derived from early stage IVF embryos in buffalo. The present experiment was carried out to study the effects of different growth factors on attachment, formation of ES cell colonies, their extent of passaging and relative expression of pluripotency marker in these colonies in buffalo. METHODS AND RESULTS For this, 8~16 cell stages zona free IVF embryos were cultured with different culture condition viz. Control, Media-I: (Control+SCF), Media-II: (Control+SCF+bFGF) and Media-III: (Control+SCF+bFGF+IGF1). A total of 25 number of embryos were cultured in each medium. The efficiency (%) of blastomere attachment, % stem cell colony formation were recorded and number of passaging were evaluated in each culture condition. The results indicated that the efficiency of embryonic blastomere attachment, % stem cell colonies formation and propagation were significantly higher when medium was supplemented with growth factors viz. SCF, bFGF and IGF-1 (Media-III) than when supplemented with either SCF or SCF+bFGF. The expression of pluripotent genes viz Oct4, Nanog, FoxD3 and KLF4 were significantly higher (p<0.005) when medium was supplemented with three growth factors. CONCLUSIONS It can be concluded that when 8~16 cell stages zona free IVF embryos of buffalo was cultured on feeder,the %of blastomere attachment, % of ES cell colony formation and their further propagation were higher in ES cell medium supplemented with SCF+bFGF+IGF1 which may be due to high expression of pluripotent stem cell markers.
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Affiliation(s)
- G. Puri
- Department of Veterinary Physiology, College of Veterinary Sciences, NAU, Navsari Gujarat
| | - Kuldeep Kumar
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - Renu Singh
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - R. K. Singh
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - T. Yasotha
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - R. Ranjan
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - Manish Kumar
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - B. C. Das
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - G. Singh
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - M. Sarkar
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
| | - Sadhan. Bag
- Division of Physiology & Climatology, Indian Veterinary Research Institute, Bareilly, India
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36
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Mesenchymal stem cells for cardiac regeneration: translation to bedside reality. Stem Cells Int 2012; 2012:646038. [PMID: 22754578 PMCID: PMC3382381 DOI: 10.1155/2012/646038] [Citation(s) in RCA: 36] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2012] [Accepted: 04/03/2012] [Indexed: 12/11/2022] Open
Abstract
Cardiovascular disease (CVD) is the leading cause of death worldwide. According to the World Health Organization (WHO), an estimate of 17.3 million people died from CVDs in 2008 and by 2030, the number of deaths is estimated to reach almost 23.6 million. Despite the development of a variety of treatment options, heart failure management has failed to inhibit myocardial scar formation and replace the lost cardiomyocyte mass with new functional contractile cells. This shortage is complicated by the limited ability of the heart for self-regeneration. Accordingly, novel management approaches have been introduced into the field of cardiovascular research, leading to the evolution of gene- and cell-based therapies. Stem cell-based therapy (aka, cardiomyoplasty) is a rapidly growing alternative for regenerating the damaged myocardium and attenuating ischemic heart disease. However, the optimal cell type to achieve this goal has not been established yet, even after a decade of cardiovascular stem cell research. Mesenchymal stem cells (MSCs) in particular have been extensively investigated as a potential therapeutic approach for cardiac regeneration, due to their distinctive characteristics. In this paper, we focus on the therapeutic applications of MSCs and their transition from the experimental benchside to the clinical bedside.
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37
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Murphy MB, Blashki D, Buchanan RM, Yazdi IK, Ferrari M, Simmons PJ, Tasciotti E. Adult and umbilical cord blood-derived platelet-rich plasma for mesenchymal stem cell proliferation, chemotaxis, and cryo-preservation. Biomaterials 2012; 33:5308-16. [PMID: 22542609 DOI: 10.1016/j.biomaterials.2012.04.007] [Citation(s) in RCA: 109] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2012] [Accepted: 04/01/2012] [Indexed: 02/07/2023]
Abstract
Platelet-rich plasma (PRP) was prepared from human adult peripheral blood and from human umbilical cord (uc) blood and the properties were compared in a series of in vitro bioassays. Quantification of growth factors in PRP and platelet-poor plasma (PPP) fractions revealed increased levels of mitogenic growth factors PDGF-AB, PDGF-BB, and FGF-2, the angiogenic agent VEGF and the chemokine RANTES in ucPRP compared to adult PRP (aPRP) and PPP. To compare the ability of the various PRP products to stimulate proliferation of human bone marrow (BM), rat BM and compact bone (CB)-derived mesenchymal stem cells (MSC), cells were cultured in serum-free media for 4 and 7 days with varying concentrations of PRP, PPP, or combinations of recombinant mitogens. It was found that while all forms of PRP and PPP were more mitogenic than fetal bovine serum, ucPRP resulted in significantly higher proliferation by 7 days than adult PRP and PPP. We observed that addition of as little as 0.1% ucPRP caused greater proliferation of MSC effects than the most potent combination of recombinant growth factors tested, namely PDGF-AB + PDGF-BB + FGF-2, each at 10 ng/mL. Similarly, in chemotaxis assays, ucPRP showed greater potency than adult PRP, PPP from either source, or indeed than combinations of either recombinant growth factors (PDGF, FGF, and TGF-β1) or chemokines previously shown to stimulate chemotactic migration of MSC. Lastly, we successfully demonstrated that PRP and PPP represented a viable alternative to FBS containing media for the cryo-preservation of MSC from human and rat BM.
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Affiliation(s)
- Matthew B Murphy
- Department of Nanomedicine, The Methodist Hospital Research Institute, Houston, TX 77025, USA
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38
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Mohsin S, Siddiqi S, Collins B, Sussman MA. Empowering adult stem cells for myocardial regeneration. Circ Res 2012; 109:1415-28. [PMID: 22158649 DOI: 10.1161/circresaha.111.243071] [Citation(s) in RCA: 82] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Treatment strategies for heart failure remain a high priority for ongoing research due to the profound unmet need in clinical disease coupled with lack of significant translational progress. The underlying issue is the same whether the cause is acute damage, chronic stress from disease, or aging: progressive loss of functional cardiomyocytes and diminished hemodynamic output. To stave off cardiomyocyte losses, a number of strategic approaches have been embraced in recent years involving both molecular and cellular approaches to augment myocardial structure and performance. Resultant excitement surrounding regenerative medicine in the heart has been tempered by realizations that reparative processes in the heart are insufficient to restore damaged myocardium to normal functional capacity and that cellular cardiomyoplasty is hampered by poor survival, proliferation, engraftment, and differentiation of the donated population. To overcome these limitations, a combination of molecular and cellular approaches must be adopted involving use of genetic engineering to enhance resistance to cell death and increase regenerative capacity. This review highlights biological properties of approached to potentiate stem cell-mediated regeneration to promote enhanced myocardial regeneration, persistence of donated cells, and long-lasting tissue repair. Optimizing cell delivery and harnessing the power of survival signaling cascades for ex vivo genetic modification of stem cells before reintroduction into the patient will be critical to enhance the efficacy of cellular cardiomyoplasty. Once this goal is achieved, then cell-based therapy has great promise for treatment of heart failure to combat the loss of cardiac structure and function associated with acute damage, chronic disease, or aging.
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39
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Haider KH, Ashraf M. Preconditioning approach in stem cell therapy for the treatment of infarcted heart. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 111:323-56. [PMID: 22917238 DOI: 10.1016/b978-0-12-398459-3.00015-0] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Nearly two decades of research in regenerative medicine have been focused on the development of stem cells as a therapeutic option for treatment of the ischemic heart. Given the ability of stem cells to regenerate the damaged tissue, stem-cell-based therapy is an ideal approach for cardiovascular disorders. Preclinical studies in experimental animal models and clinical trials to determine the safety and efficacy of stem cell therapy have produced encouraging results that promise angiomyogenic repair of the ischemically damaged heart. Despite these promising results, stem cell therapy is still confronted with issues ranging from uncertainty about the as-yet-undetermined "ideal" donor cell type to the nonoptimized cell delivery strategies to harness optimal clinical benefits. Moreover, these lacunae have significantly hampered the progress of the heart cell therapy approach from bench to bedside for routine clinical applications. Massive death of donor cells in the infarcted myocardium during acute phase postengraftment is one of the areas of prime concern, which immensely lowers the efficacy of the procedure. An overview of the published data relevant to stem cell therapy is provided here and the various strategies that have been adopted to develop and optimize the protocols to enhance donor stem cell survival posttransplantation are discussed, with special focus on the preconditioning approach.
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Affiliation(s)
- Khawaja Husnain Haider
- Department of Pathology and Laboratory Medicine, University of Cincinnati, Cincinnati, Ohio, USA
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40
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Xu M, Millard RW, Ashraf M. Role of GATA-4 in differentiation and survival of bone marrow mesenchymal stem cells. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2012; 111:217-41. [PMID: 22917233 DOI: 10.1016/b978-0-12-398459-3.00010-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cell and tissue regeneration is a relatively new research field and it incorporates a novel application of molecular genetics. Combinatorial approaches for stem-cell-based therapies wherein guided differentiation into cardiac lineage cells and cells secreting paracrine factors may be necessary to overcome the limitations and shortcomings of a singular approach. GATA-4, a GATA zinc-finger transcription factor family member, has been shown to regulate differentiation, growth, and survival of a wide range of cell types. In this chapter, we discuss whether overexpression of GATA-4 increases mesenchymal stem cell (MSC) transdifferentiation into cardiac phenotype and enhances the MSC secretome, thereby increasing cell survival and promoting postinfarction cardiac angiogenesis. MSCs engineered with GATA-4 enhance their capacity to differentiate into cardiac cell phenotypes, improve survival of the cardiac progenitor cells and their offspring, and modulate the paracrine activity of stem cells to support their angiomyogenic potential and cardioprotective effects.
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Affiliation(s)
- Meifeng Xu
- Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA
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41
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Wu KH, Mo XM, Han ZC, Zhou B. Cardiac cell therapy: pre-conditioning effects in cell-delivery strategies. Cytotherapy 2011; 14:260-6. [PMID: 22176035 DOI: 10.3109/14653249.2011.643780] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023]
Abstract
Stem-cell therapy holds great promise for the treatment of ischemic heart disease. However, the benefit of cardiac cell therapy has not yet been proven in long-term clinical trials. Poor engraftment and survival of transplanted cells is one of the major concerns for the successful application of stem cells in cardiac cell therapy. Cell and cardiac pre-conditioning are now being explored as new approaches to support cell survival and enhance the therapeutic efficacy. In this paper, we summarize the state-of-the-art methods of cell delivery and cell survival post-delivery, with a focus on the pre-conditioning approaches that have been attempted to support the survival of transplanted cells.
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Affiliation(s)
- Kai Hong Wu
- Cardiovascular Center, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China.
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42
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The combined administration of multiple soluble factors in the repair of chronically infarcted rat myocardium. J Cardiovasc Pharmacol 2011; 57:282-6. [PMID: 21383589 DOI: 10.1097/fjc.0b013e3182058717] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The purpose of this study was to investigate a potential benefit of simultaneous administration of multiple soluble factors (SFs) in the repair of chronically infarcted rat myocardium. Rats subjected to a permanent coronary artery occlusion (myocardial infarction) received a cocktail of SF or a phosphate buffer. Four SFs, fibroblast growth factor-2 (2 μg), insulin-like growth factor-1 (1 μg), hepatocyte growth factor (2 μg), and stromal cell-derived factor-1α (0.6 μg) were injected directly into the ischemic myocardium at the onset of occlusion and subsequently at 3, 7, 14, and 21 days of surgery (intraperitoneally). Cardiac contractile function, infarct size and remodeling, and blood vessel density were studied at 4 weeks postsurgery. Infarct size, left ventricular circumference and cavity volume, thinning ratio, and expansion index were not statistically different between groups. Treatment of SF did not alter ejection fraction, compared with control. No statistical difference in total blood vessel density in the infarct zone was observed in SF versus control. In conclusion, our results that there were no enhancements in cardiac function, reductions in infarct size, improvements in remodeling, or increases in vasculature density in SF versus control do not support the study hypothesis that the combined use of multiple SF benefits the hearts with myocardial infarct.
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Wu KH, Mo XM, Han ZC, Zhou B. Stem cell engraftment and survival in the ischemic heart. Ann Thorac Surg 2011; 92:1917-25. [PMID: 21955573 DOI: 10.1016/j.athoracsur.2011.07.012] [Citation(s) in RCA: 73] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/11/2011] [Revised: 07/06/2011] [Accepted: 07/12/2011] [Indexed: 11/28/2022]
Abstract
Cellular therapy has emerged as a potentially novel treatment for severe ischemic heart disease, and there is increasing evidence that stem cell transplantation may improve the perfusion and contractile function of ischemic myocardium. However, the problem of poor donor cell engraftment and survival in ischemic myocardium limits the successful use of cellular therapy for treating ischemic heart disease. This review discusses the state-of-the-art understanding of the low level of cell engraftment and cell survival after transplantation into the ischemic heart, with a focus on the approaches that have been investigated for supporting and improving the survival and engraftment of transplanted cells in this setting.
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Affiliation(s)
- Kai Hong Wu
- Department of Cardiothoracic Surgery, Nanjing Children's Hospital, Nanjing Medical University, Nanjing, China.
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44
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Effects of diosgenin on cell proliferation induced by IGF-1 in primary human thyrocytes. Arch Pharm Res 2011; 34:997-1005. [PMID: 21725821 DOI: 10.1007/s12272-011-0617-y] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2010] [Revised: 11/04/2010] [Accepted: 11/14/2010] [Indexed: 10/18/2022]
Abstract
Others and our previous studies showed that the increase of IGF-1 was involved in the formation of goiter. Our aim here was to evaluate the possible effects of diosgenin on cell proliferation induced by IGF-1 in primary human thyroid cells. The cells were treated with or without different concentrations of diosgenin in the present or absent of IGF-1 for 24, 48 and 72 h, respectively. Cell viability was determined by MTT, and cell proliferation was tested by EdU assay, and cell cycle analysis was performed by FACS. In addition, Cyclin D1 and B1 protein expression was tested by Western Blotting, respectively. We found that IGF-1 promoted cell cycle progression to S phase and increased the primary human thyroid cells proliferation. Diosgenin decreased the protein expression of cyclin D1 and resulted in cell G(0)/G(1) arrest. Importantly, when the human thyrocytes were exposed to diosgenin in the present of IGF-1, the IGF-1 inducing proliferation was significantly decreased and the proportion of the cells in G(0)/G(1) phase was increased, while that of S phase was decreased. This study shows that diosgenin inhibited cell proliferation, caused G(0)/G(1) arrest, and could inhibit cell proliferation induced by IGF-1 in primary human thyroid cells.
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45
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Abstract
Regulation of organ growth is critical during embryogenesis. At the cellular level, mechanisms controlling the size of individual embryonic organs include cell proliferation, differentiation, migration, and attrition through cell death. All these mechanisms play a role in cardiac morphogenesis, but experimental studies have shown that the major determinant of cardiac size during prenatal development is myocyte proliferation. As this proliferative capacity becomes severely restricted after birth, the number of cell divisions that occur during embryogenesis limits the growth potential of the postnatal heart. We summarize here current knowledge concerning regional control of myocyte proliferation as related to cardiac morphogenesis and dysmorphogenesis. There are significant spatial and temporal differences in rates of cell division, peaking during the preseptation period and then gradually decreasing toward birth. Analysis of regional rates of proliferation helps to explain the mechanics of ventricular septation, chamber morphogenesis, and the development of the cardiac conduction system. Proliferation rates are influenced by hemodynamic loading, and transduced by autocrine and paracrine signaling by means of growth factors. Understanding the biological response of the developing heart to such factors and physical forces will further our progress in engineering artificial myocardial tissues for heart repair and designing optimal treatment strategies for congenital heart disease.
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Affiliation(s)
- David Sedmera
- Charles University in Prague, First Faculty of Medicine, Institute of Anatomy, Prague, Czech Republic.
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Pfannkuche K, Neuss S, Pillekamp F, Frenzel LP, Attia W, Hannes T, Salber J, Hoss M, Zenke M, Fleischmann BK, Hescheler J, Sarić T. Fibroblasts facilitate the engraftment of embryonic stem cell-derived cardiomyocytes on three-dimensional collagen matrices and aggregation in hanging drops. Stem Cells Dev 2011; 19:1589-99. [PMID: 20175666 DOI: 10.1089/scd.2009.0255] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
There is growing interest in the use of cardiomyocytes purified from embryonic stem (ES) cells for tissue engineering and cardiomyoplasty. However, most transplanted cells are lost shortly after transplantation due to the lack of integration into the host tissue and subsequent apoptosis. Here we examine whether murine embryonic fibroblasts (MEFs) can support the integration of purified murine ES cell-derived cardiomyocytes in a 3-dimensional tissue culture model based on a freezed-dryed collagen matrix with tubular structure. Collagen matrix was seeded either with cardiomyocytes alone or in combination with MEFs. The collagen sponges that were transplanted with cardiomyocytes alone showed neither morphological nor functional integration of viable cells. Cardiomyocytes also did not appear to be capable of attaching quantitatively to any of 16 different 2-dimensional biomaterials. However, cardiomyocytes co-cultured with MEFs formed fiber-like structures of rod-shaped cells with organized sarcomeric structure that contracted spontaneously. Electrical coupling between cardiomyocytes was suggested by strong expression of connexin 43. In addition, MEFs as well as cardiac fibroblasts supported re-aggregation of dissociated cardiomyocytes in hanging drops in the absence of collagen matrix. We conclude that fibroblasts promote cardiomyocyte engraftment and formation of functional 3-dimensional tissue in vitro. Elucidation of the mechanism of this phenomenon may help improve the integration of cardiomyocytes in vivo.
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Affiliation(s)
- Kurt Pfannkuche
- Institute for Neurophysiology, University of Cologne, Cologne, Germany
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Zhu Y, Liu T, Ye H, Song K, Ma X, Cui Z. Enhancement of adipose-derived stem cell differentiation in scaffolds with IGF-I gene impregnation under dynamic microenvironment. Stem Cells Dev 2011; 19:1547-56. [PMID: 20408758 DOI: 10.1089/scd.2010.0054] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Biochemical and mechanical signals enabling cardiac regeneration can be elucidated by using in vitro tissue engineering models. We hypothesized that human insulin-like growth factor-I (IGF-I) and 3-dimensional (3D) dynamic microenvironment could enhance the survival and differentiation of adipose tissue-derived stem cells (ADSCs). In this study, ADSCs were cultured on 3D porous scaffolds with or without plasmid DNA PIRES2-IGF-I in cardiac media, in static culture dishes, and in a spinning flask bioreactor, respectively. Cell viability, formation of cardiac-like structure, expression of functional proteins, and gene expressions were tested in the cultured constructs on day 14. The results showed that dynamic microenvironment enhanced the release of plasmid DNA; the ADSCs can be transfected by the released plasmid DNA PIRES2-IGF-I in scaffold. IGF-I showed beneficial effects on cellular viability and increase of total protein and also increased the expressions of cardiac-specific proteins and genes in the grafts. It was also demonstrated that dynamic stirring environment could promote the proliferation of ADSCs. Therefore, IGF-I, expressed by ADSCs transfected by DNA PIRES2-IGF-I incorporated into scaffold, and hydrodynamic microenvironment can independently and interactively increase cellular viability and interactively increase the expression of cardiac-specific proteins and genes in the grafts. The results would be useful for developing tissue-engineered grafts for myocardial repair.
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Affiliation(s)
- Yanxia Zhu
- Dalian R&D Center for Stem Cell and Tissue Engineering, Dalian University of Technology, Dalian, China
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Li HY, Liao CY, Lee KH, Chang HC, Chen YJ, Chao KC, Chang SP, Cheng HY, Chang CM, Chang YL, Hung SC, Sung YJ, Chiou SH. Collagen IV significantly enhances migration and transplantation of embryonic stem cells: involvement of α2β1 integrin-mediated actin remodeling. Cell Transplant 2010; 20:893-907. [PMID: 21176409 DOI: 10.3727/096368910x550206] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Abstract
Embryonic stem (ES) cell transplantation represents a potential means for the treatment of degenerative diseases and injuries. As appropriate distribution of transplanted ES cells in the host tissue is critical for successful transplantation, the exploration of efficient strategies to enhance ES cell migration is warranted. In this study we investigated ES cell migration under the influence of various extracellular matrix (ECM) proteins, which have been shown to stimulate cell migration in various cell models with unclear effects on ES cells. Using two mouse ES (mES) cell lines, ESC 26GJ9012-8-2 and ES-D3 GL, to generate embryoid bodies (EBs), we examined the migration of differentiating cells from EBs that were delivered onto culture surfaces coated with or without collagen I, collagen IV, Matrigel, fibronectin, and laminin. Among these ECM proteins, collagen IV exhibited maximal migration enhancing effect. mES cells expressed α2 and β1 integrin subunits and the migration enhancing effect of collagen IV was prevented by RGD peptides as well as antibodies against α2 and β1 integrins, indicating that the enhancing effect of collagen IV on cell migration was mediated by α2β1 integrin. Furthermore, staining of actin cytoskeleton that links to integrins revealed well-developed stress fibers and long filopodia in mES cells cultured on collagen IV, and the actin-disrupting cytochalasin D abolished the collagen IV-enhanced cell migration. In addition, pretreatment of undifferentiated or differentiated mES cells with collagen IV resulted in improved engraftment and growth after transplantation into the subcutaneous tissue of nude mice. Finally, collagen IV pretreatment of osteogenically differentiated mES cells increased osteogenic differentiation-like tissue and decreased undifferentiation-like tissue in the grafts grown after transplantation. Our results demonstrated that collagen IV significantly enhanced the migration of differentiating ES cells through α2β1 integrin-mediated actin remodeling and could promote ES cell transplantation efficiency, which may be imperative to stem cell therapy.
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Affiliation(s)
- Hsin-Yang Li
- Department of Obstetrics and Gynecology, Taipei Veterans General Hospital, Taipei, Taiwan
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Li H, Zuo S, He Z, Yang Y, Pasha Z, Wang Y, Xu M. Paracrine factors released by GATA-4 overexpressed mesenchymal stem cells increase angiogenesis and cell survival. Am J Physiol Heart Circ Physiol 2010; 299:H1772-81. [PMID: 20870802 PMCID: PMC3006287 DOI: 10.1152/ajpheart.00557.2010] [Citation(s) in RCA: 121] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/11/2010] [Accepted: 09/17/2010] [Indexed: 01/08/2023]
Abstract
Transplanted mesenchymal stem cells (MSC) release soluble factors that contribute to cardiac repair and vascular regeneration. We hypothesized that overexpression of GATA-4 enhances the MSC secretome, thereby increasing cell survival and promoting postinfarction cardiac angiogenesis. MSCs harvested from male rat bone marrow were transduced with GATA-4 (MSC(GATA-4)) using the murine stem cell virus retroviral expression system; control cells were either nontransduced (MSC(bas)) or transduced with empty vector (MSC(Null)). Compared with these control cells, MSC(GATA-4) were shown by immunofluorescence, real-time PCR, and Western blotting to have higher expression of GATA-4. An increased expression of angiogenic factors in MSC(GATA-4) and higher MSC resistance against hypoxia were observed. Human umbilical vein endothelial cells (HUVEC) treated with MSC(GATA-4) conditioned medium exhibited increased formation of capillary-like structures and promoted migration, compared with HUVECs treated with MSC(Null) conditioned medium. MSC(GATA-4) were injected into the peri-infarct region in an acute myocardial infarction model in Sprague-Dawley rats developed by ligation of the left anterior descending coronary artery. Survival of MSC(GATA-4), determined by Sry expression, was increased at 4 days postengraftment. MSC(GATA-4)-treated animals showed significantly improved cardiac function as assessed by echocardiography. Furthermore, fluorescent microsphere and histological studies revealed increased blood flow and blood vessel density and reduced infarction size in MSC(GATA-4)-treated animals. We conclude that GATA-4 overexpression in MSCs increased both MSC survival and angiogenic potential in ischemic myocardium and may therefore represent a novel and efficient therapeutic approach for postinfarct remodeling.
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Affiliation(s)
- Hongxia Li
- Department of Pathology and Laboratory Medicine, University of Cincinnati Medical Center, Cincinnati, Ohio 45267, USA
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Liao SY, Liu Y, Siu CW, Zhang Y, Lai WH, Au KW, Lee YK, Chan YC, Yip PMC, Wu EX, Wu Y, Lau CP, Li RA, Tse HF. Proarrhythmic risk of embryonic stem cell-derived cardiomyocyte transplantation in infarcted myocardium. Heart Rhythm 2010; 7:1852-9. [PMID: 20833268 DOI: 10.1016/j.hrthm.2010.09.006] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2010] [Accepted: 09/04/2010] [Indexed: 10/19/2022]
Abstract
BACKGROUND Cellular replacement strategies using embryonic stem cells (ESCs) and their cardiac derivatives are emerging as novel experimental therapeutic paradigms for the treatment of post-myocardial infarction (MI) left ventricular (LV) dysfunction; however, their potential proarrhythmic risk remains unclear. OBJECTIVE The purpose of this study was to investigate the functional effect and proarrhythmic risk of ESC transplantation in a mouse model of MI. METHODS We compared the functional effects and proarrhythmic risk of direct intramyocardial transplantation of 3 × 10(5) undifferentiated mouse ESCs (MI+ESC group, n = 33) and mouse ESC-derived cardiomyocytes (MI+ESC-CM group, n = 40) versus culture medium (MI group, n = 33) at the infarct border zone in a mouse model of acute MI. LV performance was assessed with serial cardiac magnetic resonance imaging (MRI) at 1 and 3 week(s) post-MI, and invasive LV pressure measurement was assessed (dP/dt) at 4 weeks before sacrifice for histological examination. Furthermore, electrophysiological study was also performed in another set of animals in each group (n = 24) to assess for proarrhythmias after transplantation. RESULTS In vitro cellular electrophysiological study demonstrated that ESC-CMs exhibit arrhythmogenesis including automaticity, lengthened action potential duration, and depolarized resting membrane potential. At 4 weeks, the MI+ESC-CM group (21/40, 53%) had a higher mortality rate compared with those in the MI group (10/33, 30%, P = .08) and in the MI+ESC group (7/33, 21%, P = .012). Electrophysiological study showed a significantly higher incidence of inducible ventricular tachyarrhythmias in the MI+ESC-CM group (13/24, 54%) compared with in the MI group (6/24, 21%, P = .039) and in the MI+ESC group (5/24, 21%, P = .017). Cardiac MRI showed similar improvement in LV ejection fraction in the MI+ESC and MI+ESC-CM groups compared with in the MI group at 1 week (27.5% ± 3.8%; 30.3% ± 5.2% vs. 12.4% ± 1.4%; P < .05) and 3 weeks (29.8% ± 3.9%; 27.0% ± 4.8% vs. 10.6% ± 2.8%; P < .05) post-MI, respectively. Furthermore, invasive hemodynamic assessment at 4 weeks showed significant similar improvement in LV +dP/dt in the MI+ESC (2,644 ± 391 mmHg/s, P < .05) and MI+ESC-CM groups (2,539 ± 389 mmHg/s; P < .05) compared with in the MI group (2,042 ± 406 mmHg/s). CONCLUSIONS Our results demonstrate that transplantation of undifferentiated ESCs and ESC-CMs provides similar improvement in cardiac function post-MI. However, transplantation of ESC-CMs is associated with a significantly higher prevalence of inducible ventricular tachyarrhythmias and early mortality than transplantations with ESCs.
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Affiliation(s)
- Song-Yan Liao
- Cardiology Division, Department of Medicine, Queen Mary Hospital, University of Hong Kong, Hong Kong, Hong Kong Special Administrative Region, China
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