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Pagano F, Picchio V, Angelini F, Iaccarino A, Peruzzi M, Cavarretta E, Biondi-Zoccai G, Sciarretta S, De Falco E, Chimenti I, Frati G. The Biological Mechanisms of Action of Cardiac Progenitor Cell Therapy. Curr Cardiol Rep 2018; 20:84. [PMID: 30105430 DOI: 10.1007/s11886-018-1031-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
PURPOSE OF REVIEW Cell therapy for cardiovascular diseases is regarded as a rapidly growing field within regenerative medicine. Different cellular populations enriched for cardiac progenitor cells (CPCs), or derivate a-cellular products, are currently under preclinical and clinical evaluation. Here, we have reviewed the described mechanisms whereby resident post-natal CPCs, isolated in different ways, act as a therapeutic product on the damaged myocardium. RECENT FINDINGS Several biological mechanisms of action have been described which can explain the multiple therapeutic effects of CPC treatment observed on cardiac function and remodelling. These mechanisms span from direct cardiovascular differentiation, through induction of resident progenitor proliferation, to paracrine effects on cardiac and non-cardiac cells mediated by exosomes and non-coding RNAs. All the reported mechanisms of action support an integrated view including cardiomyogenesis, cardioprotection, and anti-fibrotic effects. Moreover, future developments of CPC therapy approaches may support cell-free strategies, exploiting effective pleiotropic cell-derived products, such as exosomes.
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Affiliation(s)
- Francesca Pagano
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Vittorio Picchio
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Francesco Angelini
- Medical Oncology Unit, San Filippo Neri Hospital, Via Giovanni Martinotti, 20, 00135, Rome, Italy
- Experimental and Clinical Pharmacology Unit, CRO-National Cancer Institute, Via Franco Gallini 2, 33081, Aviano (PN), Italy
| | - Alessandra Iaccarino
- Department of Thoracic Surgery, "La Sapienza" University of Rome, viale Regina Margherita 324, 00161, Rome, Italy
| | - Mariangela Peruzzi
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Elena Cavarretta
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Giuseppe Biondi-Zoccai
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed Institute, Via Atinense 18, 86077, Pozzilli (IS), Italy
| | - Sebastiano Sciarretta
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed Institute, Via Atinense 18, 86077, Pozzilli (IS), Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
| | - Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy.
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnologies, "La Sapienza" University of Rome, Corso della Repubblica 79, 04100, Latina, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed Institute, Via Atinense 18, 86077, Pozzilli (IS), Italy
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Matsumoto C, Jiang Y, Emathinger J, Quijada P, Nguyen N, De La Torre A, Moshref M, Nguyen J, Levinson AB, Shin M, Sussman MA, Hariharan N. Short Telomeres Induce p53 and Autophagy and Modulate Age-Associated Changes in Cardiac Progenitor Cell Fate. Stem Cells 2018; 36:868-880. [PMID: 29441645 DOI: 10.1002/stem.2793] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2017] [Revised: 01/07/2018] [Accepted: 01/24/2018] [Indexed: 12/12/2022]
Abstract
Aging severely limits myocardial repair and regeneration. Delineating the impact of age-associated factors such as short telomeres is critical to enhance the regenerative potential of cardiac progenitor cells (CPCs). We hypothesized that short telomeres activate p53 and induce autophagy to elicit the age-associated change in CPC fate. We isolated CPCs and compared mouse strains with different telomere lengths for phenotypic characteristics of aging. Wild mouse strain Mus musculus castaneus (CAST) possessing short telomeres exhibits early cardiac aging with cardiac dysfunction, hypertrophy, fibrosis, and senescence, as compared with common lab strains FVB and C57 bearing longer telomeres. CAST CPCs with short telomeres demonstrate altered cell fate as characterized by cell cycle arrest, senescence, basal commitment, and loss of quiescence. Elongation of telomeres using a modified mRNA for telomerase restores youthful properties to CAST CPCs. Short telomeres induce autophagy in CPCs, a catabolic protein degradation process, as evidenced by reduced p62 and increased accumulation of autophagic puncta. Pharmacological inhibition of autophagosome formation reverses the cell fate to a more youthful phenotype. Mechanistically, cell fate changes induced by short telomeres are partially p53 dependent, as p53 inhibition rescues senescence and commitment observed in CAST CPCs, coincident with attenuation of autophagy. In conclusion, short telomeres activate p53 and autophagy to tip the equilibrium away from quiescence and proliferation toward differentiation and senescence, leading to exhaustion of CPCs. This study provides the mechanistic basis underlying age-associated cell fate changes that will enable identification of molecular strategies to prevent senescence of CPCs. Stem Cells 2018;36:868-880.
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Affiliation(s)
- Collin Matsumoto
- Department of Pharmacology, University of California at Davis, Davis, California, USA
| | - Yan Jiang
- Department of Pharmacology, University of California at Davis, Davis, California, USA
| | | | - Pearl Quijada
- Department of Biology, San Diego State University, San Diego, California, USA
| | - Nathalie Nguyen
- Department of Biology, San Diego State University, San Diego, California, USA
| | - Andrea De La Torre
- Department of Biology, San Diego State University, San Diego, California, USA
| | - Maryam Moshref
- Department of Pharmacology, University of California at Davis, Davis, California, USA
| | - Jonathan Nguyen
- Department of Biology, San Diego State University, San Diego, California, USA
| | - Aimee B Levinson
- Department of Pharmacology, University of California at Davis, Davis, California, USA
| | - Minyoung Shin
- Department of Pharmacology, University of California at Davis, Davis, California, USA
| | - Mark A Sussman
- Department of Biology, San Diego State University, San Diego, California, USA
| | - Nirmala Hariharan
- Department of Pharmacology, University of California at Davis, Davis, California, USA.,Department of Biology, San Diego State University, San Diego, California, USA
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Platelet-Derived Growth Factor Receptor-Alpha Expressing Cardiac Progenitor Cells Can Be Derived from Previously Cryopreserved Human Heart Samples. Stem Cells Dev 2018; 27:184-198. [DOI: 10.1089/scd.2017.0082] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
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Combined Analysis of Endothelial, Hematopoietic, and Mesenchymal Stem Cell Compartments Shows Simultaneous but Independent Effects of Age and Heart Disease. Stem Cells Int 2017; 2017:5237634. [PMID: 28819363 PMCID: PMC5551513 DOI: 10.1155/2017/5237634] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2017] [Revised: 05/24/2017] [Accepted: 06/06/2017] [Indexed: 12/22/2022] Open
Abstract
Clinical trials using stem cell therapy for heart diseases have not reproduced the initial positive results obtained with animal models. This might be explained by a decreased regenerative capacity of stem cells collected from the patients. This work aimed at the simultaneous investigation of endothelial stem/progenitor cells (EPCs), mesenchymal stem/progenitor cells (MSCs), and hematopoietic stem/progenitor cells (HSCs) in sternal bone marrow samples of patients with ischemic or valvular heart disease, using flow cytometry and colony assays. The study included 36 patients referred for coronary artery bypass grafting or valve replacement surgery. A decreased frequency of stem cells was observed in both groups of patients. Left ventricular dysfunction, diabetes, and intermediate risk in EuroSCORE and SYNTAX score were associated with lower EPCs frequency, and the use of aspirin and β-blockers correlated with a higher frequency of HSCs and EPCs, respectively. Most importantly, the distribution of frequencies in the three stem cell compartments showed independent patterns. The combined investigation of the three stem cell compartments in patients with cardiovascular diseases showed that they are independently affected by the disease, suggesting the investigation of prognostic factors that may be used to determine when autologous stem cells may be used in cell therapy.
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Chimenti I, Pagano F, Sciarretta S, Marullo AGM, Greco E, Tonelli E, Peruzzi M, Cavarretta E, Biondi-Zoccai G, Frati G. Cardiac Recovery During Long-Term LVAD: Is There an Interaction Between Beta-Blockers and Cardiac Progenitor Cells? J Am Coll Cardiol 2017; 69:1880-1881. [PMID: 28385324 DOI: 10.1016/j.jacc.2016.11.092] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/15/2016] [Accepted: 11/18/2016] [Indexed: 02/05/2023]
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Kannappan R, Matsuda A, Ferreira-Martins J, Zhang E, Palano G, Czarna A, Cabral-Da-Silva MC, Bastos-Carvalho A, Sanada F, Ide N, Rota M, Blasco MA, Serrano M, Anversa P, Leri A. p53 Modulates the Fate of Cardiac Progenitor Cells Ex Vivo and in the Diabetic Heart In Vivo. EBioMedicine 2017; 16:224-237. [PMID: 28163043 PMCID: PMC5474510 DOI: 10.1016/j.ebiom.2017.01.028] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2016] [Revised: 01/20/2017] [Accepted: 01/20/2017] [Indexed: 12/01/2022] Open
Abstract
p53 is an important modulator of stem cell fate, but its role in cardiac progenitor cells (CPCs) is unknown. Here, we tested the effects of a single extra-copy of p53 on the function of CPCs in the presence of oxidative stress mediated by doxorubicin in vitro and type-1 diabetes in vivo. CPCs were obtained from super-p53 transgenic mice (p53-tg), in which the additional allele is regulated in a manner similar to the endogenous protein. Old CPCs with increased p53 dosage showed a superior ability to sustain oxidative stress, repair DNA damage and restore cell division. With doxorubicin, a larger fraction of CPCs carrying an extra-copy of the p53 allele recruited γH2A.X reestablishing DNA integrity. Enhanced p53 expression resulted in a superior tolerance to oxidative stress in vivo by providing CPCs with defense mechanisms necessary to survive in the milieu of the diabetic heart; they engrafted in regions of tissue injury and in three days acquired the cardiomyocyte phenotype. The biological advantage provided by the increased dosage of p53 in CPCs suggests that this genetic strategy may be translated to humans to increase cellular engraftment and growth, critical determinants of successful cell therapy for the failing heart.
p53 improves the ability of CPCs to sustain oxidative stress. p53 promotes the restoration of DNA integrity and cell division. p53 enhances the engraftment of CPCs in the diabetic heart. Ongoing clinical trials with autologous cardiac stem cells (CSCs) are faced with a critical limitation which is related to the modest amount of retained cells within the damaged myocardium. We have developed a strategy that overcomes in part this problem enhancing the number of CSCs able to engraft within the pathologic organ. Additionally, these genetically modified CSCs can be generated in large number, raising the possibility that multiple temporally distinct deliveries of cells can be introduced to restore the structural and functional integrity of the decompensated heart.
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Affiliation(s)
- Ramaswamy Kannappan
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Alex Matsuda
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland
| | - João Ferreira-Martins
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Eric Zhang
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Giorgia Palano
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Anna Czarna
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland
| | - Mauricio Castro Cabral-Da-Silva
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Adriana Bastos-Carvalho
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Fumihiro Sanada
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Noriko Ide
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Marcello Rota
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
| | - Maria A Blasco
- Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
| | - Manuel Serrano
- Spanish National Cancer Research Centre (CNIO), Madrid E-28029, Spain
| | - Piero Anversa
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland
| | - Annarosa Leri
- Departments of Anesthesia and Medicine, and Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA; Cardiocentro Ticino Foundation, Swiss Institute for Regenerative Medicine (SIRM), Via Tesserete 48, 6900 Lugano, Switzerland.
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Chimenti I, Pagano F, Cavarretta E, Angelini F, Peruzzi M, Barretta A, Greco E, De Falco E, Marullo AGM, Sciarretta S, Biondi-Zoccai G, Frati G. Β-blockers treatment of cardiac surgery patients enhances isolation and improves phenotype of cardiosphere-derived cells. Sci Rep 2016; 6:36774. [PMID: 27841293 PMCID: PMC5107949 DOI: 10.1038/srep36774] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 10/20/2016] [Indexed: 02/08/2023] Open
Abstract
Β-blockers (BB) are a primary treatment for chronic heart disease (CHD), resulting in prognostic and symptomatic benefits. Cardiac cell therapy represents a promising regenerative treatment and, for autologous cell therapy, the patients clinical history may correlate with the biology of resident progenitors and the quality of the final cell product. This study aimed at uncovering correlations between clinical records of biopsy-donor CHD patients undergoing cardiac surgery and the corresponding yield and phenotype of cardiospheres (CSs) and CS-derived cells (CDCs), which are a clinically relevant population for cell therapy, containing progenitors. We describe a statistically significant association between BB therapy and improved CSs yield and CDCs phenotype. We show that BB-CDCs have a reduced fibrotic-like CD90 + subpopulation, with reduced expression of collagen-I and increased expression of cardiac genes, compared to CDCs from non-BB donors. Moreover BB-CDCs had a distinctive microRNA expression profile, consistent with reduced fibrotic features (miR-21, miR-29a/b/c downregulation), and enhanced regenerative potential (miR-1, miR-133, miR-101 upregulation) compared to non-BB. In vitro adrenergic pharmacological treatments confirmed cytoprotective and anti-fibrotic effects of β1-blocker on CDCs. This study shows anti-fibrotic and pro-commitment effects of BB treatment on endogenous cardiac reparative cells, and suggests adjuvant roles of β-blockers in cell therapy applications.
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Affiliation(s)
- Isotta Chimenti
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Francesca Pagano
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Elena Cavarretta
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Francesco Angelini
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Mariangela Peruzzi
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Antonio Barretta
- Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological, and Geriatric Sciences, “Umberto I” Hospital, “La Sapienza” University of Rome, Italy
| | - Ernesto Greco
- Department of Cardiovascular, Respiratory, Nephrological, Anesthesiological, and Geriatric Sciences, “Umberto I” Hospital, “La Sapienza” University of Rome, Italy
| | - Elena De Falco
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Antonino G. M. Marullo
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
| | - Sebastiano Sciarretta
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Giuseppe Biondi-Zoccai
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
| | - Giacomo Frati
- Department of Medical Surgical Sciences and Biotechnology, “La Sapienza” University of Rome, Italy
- Department of AngioCardioNeurology, IRCCS Neuromed, Pozzilli, Italy
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Jankowski M, Broderick TL, Gutkowska J. Oxytocin and cardioprotection in diabetes and obesity. BMC Endocr Disord 2016; 16:34. [PMID: 27268060 PMCID: PMC4895973 DOI: 10.1186/s12902-016-0110-1] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Accepted: 05/18/2016] [Indexed: 12/15/2022] Open
Abstract
Oxytocin (OT) emerges as a drug for the treatment of diabetes and obesity. The entire OT system is synthesized in the rat and human heart. The direct myocardial infusion with OT into an ischemic or failing heart has the potential to elicit a variety of cardioprotective effects. OT treatment attenuates cardiomyocyte (CMs) death induced by ischemia-reperfusion by activating pro-survival pathways within injured CMs in vivo and in isolated cells. OT treatment reduces cardiac apoptosis, fibrosis, and hypertrophy. The OT/OT receptor (OTR) system is downregulated in the db/db mouse model of type 2 diabetes which develops genetic diabetic cardiomyopathy (DC) similar to human disease. We have shown that chronic OT treatment prevents the development of DC in the db/db mouse. In addition, OT stimulates glucose uptake in both cardiac stem cells and CMs, and increases cell resistance to diabetic conditions. OT may help replace lost CMs by stimulating the in situ differentiation of cardiac stem cells into functional mature CMs. Lastly, adult stem cells amenable for transplantation such as MSCs could be preconditioned with OT ex vivo and implanted into the injured heart to aid in tissue regeneration through direct differentiation, secretion of protective and cardiomyogenic factors and/or their fusion with injured CMs.
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Affiliation(s)
- Marek Jankowski
- Cardiovascular Biochemistry Laboratory, CRCHUM (7-134), Tour Viger, 900 St-Denis St., Montreal, Quebec, H2X 0A9, Canada.
- Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Canada.
| | - Tom L Broderick
- Department of Physiology, Laboratory of Diabetes and Exercise Metabolism, Midwestern University, Agave Hall, office 217-B, 19555 North 59th Avenue, Glendale, AZ, 85308, USA.
| | - Jolanta Gutkowska
- Cardiovascular Biochemistry Laboratory, CRCHUM (7-134), Tour Viger, 900 St-Denis St., Montreal, Quebec, H2X 0A9, Canada
- Department of Medicine, Faculty of Medicine, University of Montreal, Montreal, Canada
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Li GH, Luo B, Lv YX, Zheng F, Wang L, Wei MX, Li XY, Zhang L, Wang JN, Chen SY, Tang JM, He X. Dual effects of VEGF-B on activating cardiomyocytes and cardiac stem cells to protect the heart against short- and long-term ischemia-reperfusion injury. J Transl Med 2016; 14:116. [PMID: 27146579 PMCID: PMC4855341 DOI: 10.1186/s12967-016-0847-3] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/19/2016] [Accepted: 03/31/2016] [Indexed: 01/08/2023] Open
Abstract
Aims To investigate whether vascular endothelial growth factor B (VEGF-B) improves myocardial survival and cardiac stem cell (CSC) function in the ischemia–reperfusion (I/R) heart and promotes CSC mobilization and angiogenesis. Methods and results One hour after myocardial ischemia and infarction, rats were treated with recombinant human VEGF-B protein following 24 h or 7 days of myocardial reperfusion. Twenty-four hours after myocardial I/R, VEGF-B increased pAkt and Bcl-2 levels, reduced p-p38MAPK, LC3-II/I, beclin-1, CK, CK-MB and cTnt levels, triggered cardiomyocyte protection against I/R-induced autophagy and apoptosis, and contributed to the decrease of infarction size and the improvement of heart function during I/R. Simultaneously, an in vitro hypoxia-reoxygenation (H/R)-induced H9c2 cardiomyocyte injury model was used to mimic I/R injury model in vivo; in this model, VEGF-B decreased LDH release, blocked H/R-induced apoptosis by inhibiting cell autophagy, and these special effects could be abolished by the autophagy inducer, rapamycin. Mechanistically, VEGF-B markedly activated the Akt signaling pathway while slightly inhibiting p38MAPK, leading to the blockade of cell autophagy and thus protecting cardiomyocyte from H/R-induced activation of the intrinsic apoptotic pathway. Seven days after I/R, VEGF-B induced the expression of SDF-1α and HGF, resulting in the massive mobilization and homing of c-Kit positive cells, triggering further angiogenesis and vasculogenesis in the infracted heart and contributing to the improvement of I/R heart function. Conclusion VEGF-B could contribute to a favorable short- and long-term prognosis for I/R via the dual manipulation of cardiomyocytes and CSCs. Electronic supplementary material The online version of this article (doi:10.1186/s12967-016-0847-3) contains supplementary material, which is available to authorized users.
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Affiliation(s)
- Guo-Hua Li
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China.,Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Bin Luo
- Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Yan-Xia Lv
- Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Fei Zheng
- Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Lu Wang
- Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Meng-Xi Wei
- Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Xian-Yu Li
- Department of Pathophysiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Lei Zhang
- Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Jia-Ning Wang
- Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China
| | - Shi-You Chen
- Department of Physiology and Pharmacology, University of Georgia, Athens, GA, 30602, USA
| | - Jun-Ming Tang
- Department of Cardiology and Institute of Clinical Medicine, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China. .,Department of Physiology, School of Basic Medical Sciences, Hubei University of Medicine, Shiyan, Hubei Province, 442000, China.
| | - Xiaohua He
- School of Basic Medical Sciences, Wuhan University, Wuhan, 430071, Hubei Province, China.
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Abstract
Following the recognition that hematopoietic stem cells improve the outcome of myocardial infarction in animal models, bone marrow mononuclear cells, CD34-positive cells, and mesenchymal stromal cells have been introduced clinically. The intracoronary or intramyocardial injection of these cell classes has been shown to be safe and to produce a modest but significant enhancement in systolic function. However, the identification of resident cardiac stem cells in the human heart (hCSCs) has created great expectation concerning the potential implementation of this category of autologous cells for the management of the human disease. Although phase 1 clinical trials have been conducted with encouraging results, the search for the most powerful hCSC for myocardial regeneration is in its infancy. This manuscript discusses the efforts performed in our laboratory to characterize the critical biological variables that define the growth reserve of hCSCs. Based on the theory of the immortal DNA template, we propose that stem cells retaining the old DNA represent 1 of the most powerful cells for myocardial regeneration. Similarly, the expression of insulin-like growth factor-1 receptors in hCSCs recognizes a cell phenotype with superior replicating reserve. However, the impressive recovery in ventricular hemodynamics and anatomy mediated by clonal hCSCs carrying the "mother" DNA underscores the clinical relevance of this hCSC class for the treatment of human heart failure.
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Hafez P, Jose S, Chowdhury SR, Ng MH, Ruszymah BHI, Abdul Rahman Mohd R. Cardiomyogenic differentiation of human sternal bone marrow mesenchymal stem cells using a combination of basic fibroblast growth factor and hydrocortisone. Cell Biol Int 2015; 40:55-64. [PMID: 26289249 DOI: 10.1002/cbin.10536] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 08/15/2015] [Indexed: 02/05/2023]
Abstract
The alarming rate of increase in myocardial infarction and marginal success in efforts to regenerate the damaged myocardium through conventional treatments creates an exceptional avenue for cell-based therapy. Adult bone marrow mesenchymal stem cells (MSCs) can be differentiated into cardiomyocytes, by treatment with 5-azacytidine, thus, have been anticipated as a therapeutic tool for myocardial infarction treatment. In this study, we investigated the ability of basic fibroblastic growth factor (bFGF) and hydrocortisone as a combined treatment to stimulate the differentiation of MSCs into cardiomyocytes. MSCs were isolated from sternal marrow of patients undergoing heart surgery (CABG). The isolated cells were initially monitored for the growth pattern, followed by characterization using ISCT recommendations. Cells were then differentiated using a combination of bFGF and hydrocortisone and evaluated for the expression of characteristic cardiac markers such as CTnI, CTnC, and Cnx43 at protein level using immunocytochemistry and flow cytometry, and CTnC and CTnT at mRNA level. The expression levels and pattern of the cardiac markers upon analysis with ICC and qRT-PCR were similar to that of 5-azacytidine induced cells and cultured primary human cardiomyocytes. However, flow cytometric evaluation revealed that induction with bFGF and hydrocortisone drives MSC differentiation to cardiomyocytes with a marginally higher efficiency. These results indicate that combination treatment of bFGF and hydrocortisone can be used as an alternative induction method for cardiomyogenic differentiation of MSCs for future clinical applications.
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Affiliation(s)
- Pezhman Hafez
- Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - Shinsmon Jose
- Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - Shiplu R Chowdhury
- Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - Min Hwei Ng
- Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia
| | - B H I Ruszymah
- Tissue Engineering Centre, Universiti Kebangsaan Malaysia Medical Center, Kuala Lumpur, Malaysia.,Department of Physiology, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
| | - Ramzisham Abdul Rahman Mohd
- Division of Cardiothoracic Surgery, Department of Surgery, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
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14
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Abstract
Despite the increasing use of stem cells for regenerative-based cardiac therapy, the optimal stem cell population(s) remains in a cloud of uncertainty. In the past decade, the field has witnessed a surge of researchers discovering stem cell populations reported to directly and/or indirectly contribute to cardiac regeneration through processes of cardiomyogenic commitment and/or release of cardioprotective paracrine factors. This review centers upon defining basic biological characteristics of stem cells used for sustaining cardiac integrity during disease and maintenance of communication between the cardiac environment and stem cells. Given the limited successes achieved so far in regenerative therapy, the future requires development of unprecedented concepts involving combinatorial approaches to create and deliver the optimal stem cell(s) that will enhance myocardial healing.
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Affiliation(s)
- Pearl Quijada
- Integrated Regenerative Research Institute, Department of Biology, San Diego State University, 5500 Campanile Drive, San Diego, CA 92182, USA
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15
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Abstract
Stem cell therapy has the optimistic goal of regenerating the myocardium as defined by re-growth of lost or destroyed myocardium. As applied to patients with heart failure, many confuse or limit the regenerative definition to just improving myocardial function and/or decreasing myocardial scar formation, which may not be the most important clinical outcome to achieve in this promising field of molecular medicine. Many different stem cell-based therapies have been tested and have demonstrated a safe and feasible profile in adult patients with heart failure, but with varied efficacious end points reported. Although not achieved as of yet, the encompassing goal to regenerate the heart is still believed to be within reach using these cell-based therapies in adult patients with heart failure, as the first-generation therapies are now being tested in different phases of clinical trials. Similar efforts to foster the translation of stem cell therapy to children with heart failure have, however, been limited. In this review, we aim to summarise the findings from pre-clinical models and clinical experiences to date that have focussed on the evaluation of stem cell therapy in children with heart failure. Finally, we present methodological considerations pertinent to the design of a stem cell-based trial for children with heart failure, as they represent a population of patients with very different sets of issues when compared with adult patients. As has been taught by many learned clinicians, children are not small adults!
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16
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Wehman B, Sharma S, Mishra R, Guo Y, Colletti EJ, Kon ZN, Datla SR, Siddiqui OT, Balachandran K, Kaushal S. Pediatric End-Stage Failing Hearts Demonstrate Increased Cardiac Stem Cells. Ann Thorac Surg 2015; 100:615-22. [PMID: 26138767 DOI: 10.1016/j.athoracsur.2015.04.088] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2014] [Revised: 03/29/2015] [Accepted: 04/01/2015] [Indexed: 12/12/2022]
Abstract
BACKGROUND We sought to determine the location, expression, and characterization of cardiac stem cells (CSCs) in children with end-stage heart failure (ESHF). We hypothesized ESHF myocardium would contain an increased number of CSCs relative to age-matched healthy myocardium, and ESHF-derived CSCs would have diminished functional capacity as evidenced by reduced telomere length. METHODS Tissue samples were obtained from the explanted hearts of children undergoing heart transplantation with ESHF, defined as New York Heart Association class III or IV and ejection fraction less than 0.20, and from age-matched congenital heart disease patients with normal myocardium. The expression profile of cardiac-specific stem cell markers was determined using quantitative real time polymerase chain reaction and immunofluorescence. Cardiac stem cell growth reserve was assessed with telomere length. RESULTS There were 15 ESHF and 15 age-matched congenital heart disease patients. End-stage heart failure myocardium demonstrated increased expression of c-kit(+) and islet-1(+) CSCs by 2.0- and 2.5-fold, respectively, compared with myocardium from congenital heart disease patients. There was no difference in expression of c-kit(+) CSCs with advancing age from infants to children in ESHF myocardium. The c-kit(+) CSCs isolated from ESHF patients demonstrated significantly reduced telomere length, suggesting a diminished functional capability in these cells (8.1 ± 0.6 kbp versus 6.3 ± 0.3 kbp; p = 0.015). CONCLUSIONS End-stage heart failure myocardium demonstrated an age-independent increase in CSCs relative to healthy myocardium; however, these CSCs from ESHF patients may have diminished proliferative ability and reduced functionality as an autologous cell therapy candidate. Further investigation is necessary to determine the role of ESHF-derived CSCs within the myocardium.
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Affiliation(s)
- Brody Wehman
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Sudhish Sharma
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Rachana Mishra
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Yin Guo
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Evan J Colletti
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Zachary N Kon
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Srinivasa Raju Datla
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Osama T Siddiqui
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Keerti Balachandran
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland
| | - Sunjay Kaushal
- Division of Cardiac Surgery, University of Maryland School of Medicine, Baltimore, Maryland.
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17
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Gude N, Joyo E, Toko H, Quijada P, Villanueva M, Hariharan N, Sacchi V, Truffa S, Joyo A, Voelkers M, Alvarez R, Sussman MA. Notch activation enhances lineage commitment and protective signaling in cardiac progenitor cells. Basic Res Cardiol 2015; 110:29. [PMID: 25893875 DOI: 10.1007/s00395-015-0488-3] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2014] [Revised: 03/04/2015] [Accepted: 04/14/2015] [Indexed: 12/12/2022]
Abstract
Phase I clinical trials applying autologous progenitor cells to treat heart failure have yielded promising results; however, improvement in function is modest, indicating a need to enhance cardiac stem cell reparative capacity. Notch signaling plays a crucial role in cardiac development, guiding cell fate decisions that underlie myocyte and vessel differentiation. The Notch pathway is retained in the adult cardiac stem cell niche, where level and duration of Notch signal influence proliferation and differentiation of cardiac progenitors. In this study, Notch signaling promotes growth, survival and differentiation of cardiac progenitor cells into smooth muscle lineages in vitro. Cardiac progenitor cells expressing tamoxifen-regulated intracellular Notch1 (CPCeK) are significantly larger and proliferate more slowly than control cells, exhibit elevated mTORC1 and Akt signaling, and are resistant to oxidative stress. Vascular smooth muscle and cardiomyocyte markers increase in CPCeK and are augmented further upon ligand-mediated induction of Notch signal. Paracrine signals indicative of growth, survival and differentiation increase with Notch activity, while markers of senescence are decreased. Adoptive transfer of CPCeK into infarcted mouse myocardium enhances preservation of cardiac function and reduces infarct size relative to hearts receiving control cells. Greater capillary density and proportion of vascular smooth muscle tissue in CPCeK-treated hearts indicate improved vascularization. Finally, we report a previously undescribed signaling mechanism whereby Notch activation stimulates CPC growth, survival and differentiation via mTORC1 and paracrine factor expression. Taken together, these findings suggest that regulated Notch activation potentiates the reparative capacity of CPCs in the treatment of cardiac disease.
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Affiliation(s)
- Natalie Gude
- Heart Institute, and Biology Department, SDSU Integrated Regenerative Research Institute, Life Sciences North, Room 426, 5500 Campanile Drive, San Diego, CA, 92182, USA
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18
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Cardiac aging - Getting to the stem of the problem. J Mol Cell Cardiol 2015; 83:32-6. [PMID: 25886698 DOI: 10.1016/j.yjmcc.2015.04.008] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/15/2015] [Revised: 03/20/2015] [Accepted: 04/08/2015] [Indexed: 01/08/2023]
Abstract
Cardiac aging is a heterogeneous process caused by a combination of stochastic events which manifests as loss of structure and function in the heart, however several recent studies draw attention to aging being primarily a stem cell problem. This review summarizes findings in support of the "stem cell hypothesis of aging" and discusses the impact of age on cardiac stem cells and the niche. This article is part of a Special Issue entitled 'CV Aging'.
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19
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D'Amario D, Leone AM, Iaconelli A, Luciani N, Gaudino M, Kannappan R, Manchi M, Severino A, Shin SH, Graziani F, Biasillo G, Macchione A, Smaldone C, Cellini C, Siracusano A, Ottaviani L, Massetti M, Goichberg P, Leri A, Anversa P, Crea F. Response to letter regarding article, "growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery". Circulation 2015; 130:e118-9. [PMID: 25245852 DOI: 10.1161/circulationaha.114.010924] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Domenico D'Amario
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Antonio M Leone
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Antonio Iaconelli
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Nicola Luciani
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Mario Gaudino
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Ramaswamy Kannappan
- Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Melissa Manchi
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Anna Severino
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Sang Hun Shin
- Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Francesca Graziani
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Gina Biasillo
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Andrea Macchione
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Costantino Smaldone
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Carlo Cellini
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Andrea Siracusano
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Lara Ottaviani
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Massimo Massetti
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
| | - Polina Goichberg
- Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Annarosa Leri
- Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Piero Anversa
- Departments of Anesthesia and Medicine, Division of Cardiovascular Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA
| | - Filippo Crea
- Department of Cardiovascular Sciences, Catholic University of the Sacred Heart, Rome, Italy
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20
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Page BJ, Banas MD, Suzuki G, Weil BR, Young RF, Fallavollita JA, Palka BA, Canty JM. Revascularization of chronic hibernating myocardium stimulates myocyte proliferation and partially reverses chronic adaptations to ischemia. J Am Coll Cardiol 2015; 65:684-97. [PMID: 25677430 DOI: 10.1016/j.jacc.2014.11.040] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2014] [Revised: 11/05/2014] [Accepted: 11/11/2014] [Indexed: 12/30/2022]
Abstract
BACKGROUND The time course and extent of recovery after revascularization of viable dysfunctional myocardium are variable. Although fibrosis is a major determinant, myocyte structural and molecular remodeling may also play important roles. OBJECTIVES This study sought to determine whether persistent myocyte loss and/or irreversibility of protein changes that develop in hibernating myocardium have an impact on functional recovery in the absence of infarction. METHODS Swine implanted with a chronic left anterior descending artery (LAD) stenosis to produce hibernating myocardium underwent percutaneous revascularization, with serial functional recovery evaluated for 1 month (n = 12). Myocardial tissue was evaluated to assess myocyte size, nuclear density, and proliferation indexes in comparison with those of normal animals and nonrevascularized controls. Proteomic analysis by 2-dimensional differential in-gel electrophoresis was used to determine the reversibility of molecular adaptations of hibernating myocytes. RESULTS At 3 months, physiological features of hibernating myocardium were confirmed, with depressed LAD wall thickening and no significant infarction. Revascularization normalized LAD flow reserve, with no immediate change in LAD wall thickening. Regional LAD wall thickening slowly improved but remained depressed 1 month post-percutaneous coronary intervention. Surprisingly, revascularization was associated with histological evidence of myocytes re-entering the growth phase of the cell cycle and increases in the number of c-Kit(+) cells. Myocyte nuclear density returned to normal, whereas regional myocyte hypertrophy regressed. Proteomic analysis demonstrated heterogeneous effects of revascularization. Up-regulated stress and cytoskeletal proteins normalized, whereas reduced contractile and metabolic proteins persisted. CONCLUSIONS Delayed recovery of hibernating myocardium in the absence of scar may reflect persistent reductions in the amounts of contractile and metabolic proteins. Although revascularization appeared to stimulate myocyte proliferation, the persistence of small immature myocytes may have contributed to delayed functional recovery.
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Affiliation(s)
- Brian J Page
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York
| | - Michael D Banas
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York
| | - Gen Suzuki
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York
| | - Brian R Weil
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York
| | - Rebeccah F Young
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York
| | - James A Fallavollita
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York; VA Western New York Health Care System, Buffalo, New York
| | - Beth A Palka
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York
| | - John M Canty
- UB Clinical and Translational Research Center and Department of Medicine, University at Buffalo, Buffalo, New York; VA Western New York Health Care System, Buffalo, New York; Department of Physiology and Biophysics and Department of Biomedical Engineering, University at Buffalo, Buffalo, New York.
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21
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Kim JT, Chung HJ, Seo JY, Yang YI, Choi MY, Kim HI, Yang TH, Lee WJ, Youn YC, Kim HJ, Kim YM, Lee H, Jang YS, Lee SJ. A fibrin-supported myocardial organ culture for isolation of cardiac stem cells via the recapitulation of cardiac homeostasis. Biomaterials 2015; 48:66-83. [DOI: 10.1016/j.biomaterials.2015.01.041] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Revised: 01/11/2015] [Accepted: 01/20/2015] [Indexed: 12/22/2022]
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22
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Hilberath JN, Sotillo CL, Muehlschlegel JD. Noteworthy articles in 2014 for cardiothoracic anesthesiologists. Semin Cardiothorac Vasc Anesth 2015; 19:6-11. [PMID: 25608971 DOI: 10.1177/1089253214568530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
In 2014, cardiothoracic anesthesiology again generated high-quality scientific work published in highly regarded journals. Our specialty continues to make significant strides in the creation and implementation of protocols to improve outcomes in our patients, which undoubtedly contribute to a safer hospital environment for patients and employees alike. Another theme that stirred a lot of interest in the past year is the search for patient-centered treatment plans. Even though we are still some time away from truly personalized medicine, our specialty starts to ask and answer exciting questions: Would we treat patient A any different from patient B if their genetic profiles were easily accessible? Could individualized treatment choices influence our patients' immediate and long-term outcomes? For this review, we selected a sample of relevant contributions to the field of cardiothoracic anesthesiology in 2014 with potential impact on our clinical routine.
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Affiliation(s)
- Jan N Hilberath
- Department of Anesthesiology and Critical Care Medicine, Eberhard Karls University, Tübingen, Germany
| | - Claudia L Sotillo
- Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
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23
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Saeed M, Hetts SW, Jablonowski R, Wilson MW. Magnetic resonance imaging and multi-detector computed tomography assessment of extracellular compartment in ischemic and non-ischemic myocardial pathologies. World J Cardiol 2014; 6:1192-1208. [PMID: 25429331 PMCID: PMC4244616 DOI: 10.4330/wjc.v6.i11.1192] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Revised: 08/15/2014] [Accepted: 09/10/2014] [Indexed: 02/06/2023] Open
Abstract
Myocardial pathologies are major causes of morbidity and mortality worldwide. Early detection of loss of cellular integrity and expansion in extracellular volume (ECV) in myocardium is critical to initiate effective treatment. The three compartments in healthy myocardium are: intravascular (approximately 10% of tissue volume), interstitium (approximately 15%) and intracellular (approximately 75%). Myocardial cells, fibroblasts and vascular endothelial/smooth muscle cells represent intracellular compartment and the main proteins in the interstitium are types I/III collagens. Microscopic studies have shown that expansion of ECV is an important feature of diffuse physiologic fibrosis (e.g., aging and obesity) and pathologic fibrosis [heart failure, aortic valve disease, hypertrophic cardiomyopathy, myocarditis, dilated cardiomyopathy, amyloidosis, congenital heart disease, aortic stenosis, restrictive cardiomyopathy (hypereosinophilic and idiopathic types), arrythmogenic right ventricular dysplasia and hypertension]. This review addresses recent advances in measuring of ECV in ischemic and non-ischemic myocardial pathologies. Magnetic resonance imaging (MRI) has the ability to characterize tissue proton relaxation times (T1, T2, and T2*). Proton relaxation times reflect the physical and chemical environments of water protons in myocardium. Delayed contrast enhanced-MRI (DE-MRI) and multi-detector computed tomography (DE-MDCT) demonstrated hyper-enhanced infarct, hypo-enhanced microvascular obstruction zone and moderately enhanced peri-infarct zone, but are limited for visualizing diffuse fibrosis and patchy microinfarct despite the increase in ECV. ECV can be measured on equilibrium contrast enhanced MRI/MDCT and MRI longitudinal relaxation time mapping. Equilibrium contrast enhanced MRI/MDCT and MRI T1 mapping is currently used, but at a lower scale, as an alternative to invasive sub-endomyocardial biopsies to eliminate the need for anesthesia, coronary catheterization and possibility of tissue sampling error. Similar to delayed contrast enhancement, equilibrium contrast enhanced MRI/MDCT and T1 mapping is completely noninvasive and may play a specialized role in diagnosis of subclinical and other myocardial pathologies. DE-MRI and when T1-mapping demonstrated sub-epicardium, sub-endocardial and patchy mid-myocardial enhancement in myocarditis, Behcet’s disease and sarcoidosis, respectively. Furthermore, recent studies showed that the combined technique of cine, T2-weighted and DE-MRI technique has high diagnostic accuracy for detecting myocarditis. When the tomographic techniques are coupled with myocardial perfusion and left ventricular function they can provide valuable information on the progression of myocardial pathologies and effectiveness of new therapies.
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24
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Li Y, Shen Z. Letter by Li and Shen regarding article, "growth properties of cardiac stem cells are a novel biomarker of patients' outcome after coronary bypass surgery". Circulation 2014; 130:e117. [PMID: 25245851 DOI: 10.1161/circulationaha.113.008500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Yangxin Li
- Department of Cardiovascular Surgery & Institute of Cardiovascular Science, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China
| | - Zhenya Shen
- Department of Cardiovascular Surgery & Institute of Cardiovascular Science, First Affiliated Hospital of Soochow University, Suzhou, Jiangsu, P.R. China
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25
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Affiliation(s)
- Sadia Mohsin
- San Diego Heart Research Institute, San Diego State University, San Diego, CA (S.M., M.A.S.); and Stanford Cardiovascular Institute, Stanford University School of Medicine, Stanford, CA (J.C.W.)
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