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1
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Yao J, Ma F, Zhang L, Zhu C, Jumabay M, Yao Z, Wang L, Cai X, Zhang D, Qiao X, Shivkumar K, Pellegrini M, Yao Y, Wu X, Boström KI. Single-Cell RNA-Seq Identifies Dynamic Cardiac Transition Program from Adipose Derived Cells Induced by Leukemia Inhibitory Factor. Stem Cells 2022; 40:932-948. [PMID: 35896368 PMCID: PMC9585902 DOI: 10.1093/stmcls/sxac048] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2022] [Accepted: 06/22/2022] [Indexed: 11/13/2022]
Abstract
Adipose-derived cells (ADCs) from white adipose tissue (WAT) are promising stem cell candidates because of their large regenerative reserves and the potential for cardiac regeneration. However, given the heterogeneity of ADC and its unsolved mechanisms of cardiac acquisition, ADC-cardiac transition efficiency remains low. In this study, we explored the heterogeneity of ADCs and the cellular kinetics of 39,432 single-cell transcriptomes along the leukemia inhibitory factor (LIF) induced ADC-cardiac transition. We identified distinct ADC subpopulations that reacted differentially to LIF when entering the cardiomyogenic program, further demonstrating that ADC-myogenesis is time-dependent and initiates from transient changes in nuclear factor erythroid 2-related factor 2 (Nrf2) signaling. At later stages, pseudotime analysis of ADCs navigated a trajectory with two branches corresponding to activated myofibroblast or cardiomyocyte-like cells. Our findings offer a high-resolution dissection of ADC heterogeneity and cell fate during ADC-cardiac transition, thus providing new insights into potential cardiac stem cells.
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Affiliation(s)
- Jiayi Yao
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Feiyang Ma
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA.,Chongqing International Institute for Immunology, Chongqing 401338, China
| | - Li Zhang
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Ching Zhu
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Medet Jumabay
- Division of Allergy, Immunology Center for Immunity, Infection, and Inflammation Pediatrics, Dept of Medicine, University of California, San Diego, San Diego, CA
| | - Zehao Yao
- Peking Union Medical College, Chinese Academy of Medical Science & Peking Union Medical College, Beijing, China
| | - Lumin Wang
- Institute of Precision Medicine, the Second Affiliated Hospital of Xi'an Jiaotong University, Xi'an, China
| | - Xinjiang Cai
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Daoqin Zhang
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Xiaojing Qiao
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | | | - Matteo Pellegrini
- Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA.,Dept of Molecular, Cell and Developmental Biology, University of California, Los Angeles, CA
| | - Yucheng Yao
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Xiuju Wu
- Division of Cardiology, David Geffen School of Medicine at UCLA
| | - Kristina I Boström
- Division of Cardiology, David Geffen School of Medicine at UCLA.,Molecular Biology Institute, University of California, Los Angeles, Los Angeles, CA
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2
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022; 14:1-40. [PMID: 35126826 PMCID: PMC8788183 DOI: 10.4252/wjsc.v14.i1.1] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Revised: 07/02/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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3
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Mehanna RA, Essawy MM, Barkat MA, Awaad AK, Thabet EH, Hamed HA, Elkafrawy H, Khalil NA, Sallam A, Kholief MA, Ibrahim SS, Mourad GM. Cardiac stem cells: Current knowledge and future prospects. World J Stem Cells 2022. [PMID: 35126826 DOI: 10.4252/wjsc.v14.i1.1]] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Regenerative medicine is the field concerned with the repair and restoration of the integrity of damaged human tissues as well as whole organs. Since the inception of the field several decades ago, regenerative medicine therapies, namely stem cells, have received significant attention in preclinical studies and clinical trials. Apart from their known potential for differentiation into the various body cells, stem cells enhance the organ's intrinsic regenerative capacity by altering its environment, whether by exogenous injection or introducing their products that modulate endogenous stem cell function and fate for the sake of regeneration. Recently, research in cardiology has highlighted the evidence for the existence of cardiac stem and progenitor cells (CSCs/CPCs). The global burden of cardiovascular diseases' morbidity and mortality has demanded an in-depth understanding of the biology of CSCs/CPCs aiming at improving the outcome for an innovative therapeutic strategy. This review will discuss the nature of each of the CSCs/CPCs, their environment, their interplay with other cells, and their metabolism. In addition, important issues are tackled concerning the potency of CSCs/CPCs in relation to their secretome for mediating the ability to influence other cells. Moreover, the review will throw the light on the clinical trials and the preclinical studies using CSCs/CPCs and combined therapy for cardiac regeneration. Finally, the novel role of nanotechnology in cardiac regeneration will be explored.
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Affiliation(s)
- Radwa A Mehanna
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa M Essawy
- Oral Pathology Department, Faculty of Dentistry/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Mona A Barkat
- Human Anatomy and Embryology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ashraf K Awaad
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Eman H Thabet
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Heba A Hamed
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Hagar Elkafrawy
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Nehal A Khalil
- Medical Biochemistry Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Abeer Sallam
- Medical Physiology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Marwa A Kholief
- Forensic Medicine and Clinical toxicology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Samar S Ibrahim
- Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt
| | - Ghada M Mourad
- Histology and Cell Biology Department/Center of Excellence for Research in Regenerative Medicine and Applications, Faculty of Medicine, Alexandria University, Alexandria 21500, Egypt.
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Jafarizade M, Kahe F, Sharfaei S, Momenzadeh K, Pitliya A, Zahedi Tajrishi F, Singh P, Chi G. The Role of Interleukin-27 in Atherosclerosis: A Contemporary Review. Cardiology 2021; 146:517-530. [PMID: 34010834 DOI: 10.1159/000515359] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Accepted: 02/16/2021] [Indexed: 11/19/2022]
Abstract
Atherosclerosis is a chronic inflammation characterized by an imbalance between inhibitors and stimulators of the inflammatory system that leads to the formation of atherosclerotic plaques in the vessel walls. Interleukin (IL)-27 is one of the recently discovered cytokines that have an immunomodulatory role in autoimmune and inflammatory diseases. However, the definite role of IL-27 in the pathogenesis of atherosclerosis remains unclear. Recent studies on cardiomyocytes and vascular endothelium have demonstrated mechanisms through which IL-27 could potentially modulate atherosclerosis. Upregulation of the IL-27 receptor was also observed in the atherosclerotic plaques. In addition, circulatory IL-27 levels were increased in patients with acute coronary syndrome and myocardial infarction. A regenerative, neovascularization, and cardioprotective role of IL-27 has also been implicated. Future studies are warranted to elucidate the biologic function and clinical significance of IL-27 in atherosclerosis.
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Affiliation(s)
| | - Farima Kahe
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Sadaf Sharfaei
- Baim Institute for Clinical Research, Boston, Massachusetts, USA
| | - Kaveh Momenzadeh
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
| | - Anmol Pitliya
- West Virginia University College of Medicine/Camden Clark Medical Center, Parkersburg, West Virginia, USA
| | | | - Preeti Singh
- Mass General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Gerald Chi
- Division of Cardiovascular Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA
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5
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Passaro F, Testa G. Implications of Cellular Aging in Cardiac Reprogramming. Front Cardiovasc Med 2018; 5:43. [PMID: 29755986 PMCID: PMC5935013 DOI: 10.3389/fcvm.2018.00043] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2018] [Accepted: 04/20/2018] [Indexed: 01/02/2023] Open
Abstract
Aging is characterized by a chronic functional decline of organ systems which leads to tissue dysfunction over time, representing a risk factor for diseases development, including cardiovascular. The aging process occurring in the cardiovascular system involves heart and vessels at molecular and cellular level, with subsequent structural modifications and functional impairment. Several modifications involved in the aging process can be ascribed to cellular senescence, a biological response that limits the proliferation of damaged cells. In physiological conditions, the mechanism of cellular senescence is involved in regulation of tissue homeostasis, remodeling, and repair. However, in some conditions senescence-driven tissue repair may fail, leading to the tissue accumulation of senescent cells which in turn may contribute to tumor promotion, aging, and age-related diseases. Cellular reprogramming processes can reverse several age-associated cell features, such as telomere length, DNA methylation, histone modifications and cell-cycle arrest. As such, induced Pluripotent Stem Cells (iPSCs) can provide models of progeroid and physiologically aged cells to gain insight into the pathogenesis of such conditions, to drive the development of new therapies for premature aging and to further explore the possibility of rejuvenating aged cells. An emerging picture is that the tissue remodeling role of cellular senescence could also be crucial for the outcomes of in vivo reprogramming processes. Experimental evidence has demonstrated that, on one hand, senescence represents a cell-autonomous barrier for a cell candidate to reprogramming, but, on the other hand, it may positively sustain the reprogramming capability of surrounding cells to generate fully proficient tissues. This review fits into this conceptual framework by highlighting the most prominent concepts that characterize aging and reprogramming and discusses how the aging tissue might provide a favorable microenvironment for in vivo cardiac reprogramming.
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Affiliation(s)
- Fabiana Passaro
- Department of Molecular Medicine and Medical Biotechnology, University of Naples "Federico II", Napoli, Italy
| | - Gianluca Testa
- Interdepartmental Center for Nanotechnology Research - NanoBem, University of Molise, Campobasso, Italy.,Department of Medicine and Health Sciences "Vincenzo Tiberio", University of Molise, Campobasso, Italy
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6
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Singh A, Singh A, Sen D. Mesenchymal stem cells in cardiac regeneration: a detailed progress report of the last 6 years (2010-2015). Stem Cell Res Ther 2016; 7:82. [PMID: 27259550 PMCID: PMC4893234 DOI: 10.1186/s13287-016-0341-0] [Citation(s) in RCA: 154] [Impact Index Per Article: 17.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022] Open
Abstract
Mesenchymal stem cells have been used for cardiovascular regenerative therapy for decades. These cells have been established as one of the potential therapeutic agents, following several tests in animal models and clinical trials. In the process, various sources of mesenchymal stem cells have been identified which help in cardiac regeneration by either revitalizing the cardiac stem cells or revascularizing the arteries and veins of the heart. Although mesenchymal cell therapy has achieved considerable admiration, some challenges still remain that need to be overcome in order to establish it as a successful technique. This in-depth review is an attempt to summarize the major sources of mesenchymal stem cells involved in myocardial regeneration, the significant mechanisms involved in the process with a focus on studies (human and animal) conducted in the last 6 years and the challenges that remain to be addressed.
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Affiliation(s)
- Aastha Singh
- School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Abhishek Singh
- School of Bio Sciences and Technology, VIT University, Vellore, India
| | - Dwaipayan Sen
- School of Bio Sciences and Technology, VIT University, Vellore, India. .,Cellular and Molecular Therapeutics Laboratory, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), VIT University, Vellore, 632014, Tamil Nadu, India.
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7
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Understanding STAT3 signaling in cardiac ischemia. Basic Res Cardiol 2016; 111:27. [PMID: 27017613 DOI: 10.1007/s00395-016-0543-8] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/01/2015] [Revised: 01/25/2016] [Accepted: 02/17/2016] [Indexed: 10/22/2022]
Abstract
Cardiovascular disease is the leading cause of death worldwide. It remains one of the greatest challenges to global health and will continue to dominate mortality trends in the future. Acute myocardial infarction results in 7.4 million deaths globally per annum. Current management strategies are centered on restoration of coronary blood flow via percutaneous coronary intervention, coronary artery bypass grafting and administration of anti-platelet agents. Such myocardial reperfusion accounts for 40-50 % of the final infarct size in most cases. Signaling transducer and activator of transcription 3 (STAT3) has been shown to have cardioprotective effects via canonical and non-canonical activation and modulation of mitochondrial and transcriptional responses. A significant body of in vitro and in vivo evidence suggests that activation of the STAT3 signal transduction pathway results in a cardio protective response to ischemia and attempts have been made to modulate this with therapeutic effect. Not only is STAT3 important for cardiomyocyte function, but it also modulates the cardiac microenvironment and communicates with cardiac fibroblasts. To this end, we here review the current evidence supporting the manipulation of STAT3 for therapeutic benefit in cardiac ischemia and identify areas for future research.
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8
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Albulescu R, Tanase C, Codrici E, Popescu DI, Cretoiu SM, Popescu LM. The secretome of myocardial telocytes modulates the activity of cardiac stem cells. J Cell Mol Med 2015; 19:1783-1794. [PMID: 26176909 PMCID: PMC4549029 DOI: 10.1111/jcmm.12624] [Citation(s) in RCA: 97] [Impact Index Per Article: 9.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2015] [Accepted: 05/06/2015] [Indexed: 02/05/2023] Open
Abstract
Telocytes (TCs) are interstitial cells that are present in numerous organs, including the heart interstitial space and cardiac stem cell niche. TCs are completely different from fibroblasts. TCs release extracellular vesicles that may interact with cardiac stem cells (CSCs) via paracrine effects. Data on the secretory profile of TCs and the bidirectional shuttle vesicular signalling mechanism between TCs and CSCs are scarce. We aimed to characterize and understand the in vitro effect of the TC secretome on CSC fate. Therefore, we studied the protein secretory profile using supernatants from mouse cultured cardiac TCs. We also performed a comparative secretome analysis using supernatants from rat cultured cardiac TCs, a pure CSC line and TCs-CSCs in co-culture using (i) high-sensitivity on-chip electrophoresis, (ii) surface-enhanced laser desorption/ionization time-of-flight mass spectrometry and (iii) multiplex analysis by Luminex-xMAP. We identified several highly expressed molecules in the mouse cardiac TC secretory profile: interleukin (IL)-6, VEGF, macrophage inflammatory protein 1α (MIP-1α), MIP-2 and MCP-1, which are also present in the proteome of rat cardiac TCs. In addition, rat cardiac TCs secrete a slightly greater number of cytokines, IL-2, IL-10, IL-13 and some chemokines like, GRO-KC. We found that VEGF, IL-6 and some chemokines (all stimulated by IL-6 signalling) are secreted by cardiac TCs and overexpressed in co-cultures with CSCs. The expression levels of MIP-2 and MIP-1α increased twofold and fourfold, respectively, when TCs were co-cultured with CSCs, while the expression of IL-2 did not significantly differ between TCs and CSCs in mono culture and significantly decreased (twofold) in the co-culture system. These data suggest that the TC secretome plays a modulatory role in stem cell proliferation and differentiation.
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Affiliation(s)
- Radu Albulescu
- Biochemistry-Proteomics Department, Victor Babeş National Institute of PathologyBucharest, Romania
- National Institute for Chemical Pharmaceutical Research & DevelopmentBucharest, Romania
| | - Cristiana Tanase
- Biochemistry-Proteomics Department, Victor Babeş National Institute of PathologyBucharest, Romania
| | - Elena Codrici
- Biochemistry-Proteomics Department, Victor Babeş National Institute of PathologyBucharest, Romania
| | - Daniela I Popescu
- Biochemistry-Proteomics Department, Victor Babeş National Institute of PathologyBucharest, Romania
| | - Sanda M Cretoiu
- Division of Cell Biology and Histology, Carol Davila University of Medicine and PharmacyBucharest, Romania
- Department of Ultrastructural Pathology, Victor Babeş National Institute of PathologyBucharest, Romania
| | - Laurentiu M Popescu
- Division of Cell Biology and Histology, Carol Davila University of Medicine and PharmacyBucharest, Romania
- Department of Advanced Studies, Victor Babeş National Institute of PathologyBucharest, Romania
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Cardiopulmonary Bypass Decreases Activation of the Signal Transducer and Activator of Transcription 3 (STAT3) Pathway in Diabetic Human Myocardium. Ann Thorac Surg 2015; 100:1636-45; discussion 1645. [PMID: 26228595 DOI: 10.1016/j.athoracsur.2015.05.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 05/01/2015] [Accepted: 05/05/2015] [Indexed: 01/03/2023]
Abstract
BACKGROUND Cardiopulmonary bypass (CPB) is associated with increased myocardial oxidative stress and apoptosis in diabetic patients. A mechanistic understanding of this relationship could have therapeutic value. To establish a possible mechanism, we compared the activation of the cardioprotective signal transducer and activator of transcription 3 (STAT3) pathway between patients with uncontrolled diabetes (UD) and nondiabetic (ND) patients. METHODS Right atrial tissue and serum were collected before and after CPB from 80 patients, 39 ND and 41 UD (HbA1c ≥ 6.5), undergoing cardiac operations. The samples were evaluated with Western blotting, immunohistochemistry, and microarray. RESULTS On Western blot, leptin levels were significantly increased in ND post-CPB (p < 0.05). Compared with ND, the expression of Janus kinase 2 and phosphorylation (p-) of STAT3 was significantly decreased in UD (p < 0.05). The apoptotic proteins p-Bc12/Bc12 and caspase 3 were significantly increased (p < 0.05), antiapoptotic proteins Mcl-1, Bcl-2, and p-Akt were significantly decreased (p < 0.05) in UD compared with ND. The microarray data suggested significantly increased expression of interleukin-6 R, proapoptotic p-STAT1, caspase 9, and decreased expression of Bc12 and protein inhibitor of activated STAT1 antiapoptotic genes (p = 0.05) in the UD patients. The oxidative stress marker nuclear factor-κB was significantly higher (p < 0.05) in UD patients post-CPB compared with the pre-CPB value, but was decreased, albeit insignificantly, in ND patients post-CPB. CONCLUSIONS Compared with ND, UD myocardium demonstrated attenuation of the cardioprotective STAT3 pathway. Identification of this mechanism offers a possible target for therapeutic modulation.
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10
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Tanaka T, Obana M, Mohri T, Ebara M, Otani Y, Maeda M, Fujio Y. Interleukin-27 induces the endothelial differentiation in Sca-1+ cardiac resident stem cells. Cytokine 2015; 75:365-72. [PMID: 26142823 DOI: 10.1016/j.cyto.2015.06.009] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2015] [Revised: 06/12/2015] [Accepted: 06/12/2015] [Indexed: 10/23/2022]
Abstract
Cytokines play important roles in cardiac repair and regeneration. Recently, we demonstrated that interleukin (IL)-6 family cytokines induce the endothelial differentiation of Sca-1+ cardiac resident stem cells through STAT3/Pim-1 signaling pathway. In contrast, the biological functions of IL-12 family cytokines in heart remain to be elucidated, though they show structural homology with IL-6. In the present study, we examined the effects of IL-12 family cytokines on the transdifferentiation of cardiac Sca-1+ cells into cardiac cells. RT-PCR analyses revealed that IL-27 receptor α (IL-27Rα), but not IL-12R or IL-23R, was expressed in cardiac Sca-1+ cells. The transcript expression of IL-27 was elevated in murine hearts in cardiac injury models. Intriguingly, IL-27 stimulation for 14 days induced the endothelial cell (EC) marker genes, such as CD-31 and VE-cadherin. Immunoblot analyses clarified that IL-27 treatment rapidly phosphorylated STAT3. IL-27 upregulated the expression of Pim-1, but the overexpression of dominant negative STAT3 abrogated the induction of Pim-1 by IL-27. Finally, adenoviral transfection of dominant negative Pim-1 inhibited IL-27-induced EC differentiation of cardiac Sca-1+ cells. These findings demonstrated that IL-27 promoted the commitment of cardiac stem cells into the EC lineage, possibly leading to neovascularization as a novel biological function. IL-27 could not only regulate the inflammation but also contribute to the maintenance of the tissue homeostasis through stem cell differentiation at inflammatory sites.
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Affiliation(s)
- Tomohiro Tanaka
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan
| | - Masanori Obana
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan
| | - Tomomi Mohri
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan
| | - Masaki Ebara
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan
| | - Yuta Otani
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan
| | - Makiko Maeda
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan
| | - Yasushi Fujio
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita City, Osaka 565-0871, Japan.
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11
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Pagliari S, Jelinek J, Grassi G, Forte G. Targeting pleiotropic signaling pathways to control adult cardiac stem cell fate and function. Front Physiol 2014; 5:219. [PMID: 25071583 PMCID: PMC4076671 DOI: 10.3389/fphys.2014.00219] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2014] [Accepted: 05/26/2014] [Indexed: 11/13/2022] Open
Abstract
The identification of different pools of cardiac progenitor cells resident in the adult mammalian heart opened a new era in heart regeneration as a means to restore the loss of functional cardiac tissue and overcome the limited availability of donor organs. Indeed, resident stem cells are believed to participate to tissue homeostasis and renewal in healthy and damaged myocardium although their actual contribution to these processes remain unclear. The poor outcome in terms of cardiac regeneration following tissue damage point out at the need for a deeper understanding of the molecular mechanisms controlling CPC behavior and fate determination before new therapeutic strategies can be developed. The regulation of cardiac resident stem cell fate and function is likely to result from the interplay between pleiotropic signaling pathways as well as tissue- and cell-specific regulators. Such a modular interaction-which has already been described in the nucleus of a number of different cells where transcriptional complexes form to activate specific gene programs-would account for the unique responses of cardiac progenitors to general and tissue-specific stimuli. The study of the molecular determinants involved in cardiac stem/progenitor cell regulatory mechanisms may shed light on the processes of cardiac homeostasis in health and disease and thus provide clues on the actual feasibility of cardiac cell therapy through tissue-specific progenitors.
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Affiliation(s)
- Stefania Pagliari
- Integrated Center for Cell Therapy and Regenerative Medicine (ICCT), International Clinical Research Center, St. Anne's University HospitalBrno, Czech Republic
| | - Jakub Jelinek
- Integrated Center for Cell Therapy and Regenerative Medicine (ICCT), International Clinical Research Center, St. Anne's University HospitalBrno, Czech Republic
| | - Gabriele Grassi
- Department of Life Sciences, University of TriesteTrieste, Italy
| | - Giancarlo Forte
- Integrated Center for Cell Therapy and Regenerative Medicine (ICCT), International Clinical Research Center, St. Anne's University HospitalBrno, Czech Republic
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12
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Abstract
Recently various kinds of cardiac stem/progenitor cells have been identified and suggested to be involved in cardiac repair and regeneration in injured myocardium. In this review, we focus on the roles of JAK-STAT signaling in cardiac stem/progenitor cells in cardiomyogenesis. JAK-STAT signaling plays important roles in the differentiation of stem cells into cardiac lineage cells. The activation of JAK-STAT signal elicits the mobilization of mesenchymal stem cells as well, contributing to the maintenance of cardiac function. Thus we propose that JAK-STAT could be a target signaling pathway in cardiac regenerative therapy.
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Affiliation(s)
- Tomomi Mohri
- Laboratory of Clinical Science and Biomedicine; Graduate School of Pharmaceutical Sciences; Osaka University; Osaka, Japan
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13
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Role of adenosine A2B receptor signaling in contribution of cardiac mesenchymal stem-like cells to myocardial scar formation. Purinergic Signal 2014; 10:477-86. [PMID: 24584483 DOI: 10.1007/s11302-014-9410-y] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2013] [Accepted: 02/18/2014] [Indexed: 12/20/2022] Open
Abstract
Adenosine levels increase in ischemic hearts and contribute to the modulation of that pathological environment. We previously showed that A2B adenosine receptors on mouse cardiac Sca1(+)CD31(-) mesenchymal stromal cells upregulate secretion of paracrine factors that may contribute to the improvement in cardiac recovery seen when these cells are transplanted in infarcted hearts. In this study, we tested the hypothesis that A2B receptor signaling regulates the transition of Sca1(+)CD31(-) cells, which occurs after myocardial injury, into a myofibroblast phenotype that promotes myocardial repair and remodeling. In vitro, TGFβ1 induced the expression of the myofibroblast marker α-smooth muscle actin (αSMA) and increased collagen I generation in Sca1(+)CD31(-) cells. Stimulation of A2B receptors attenuated TGFβ1-induced collagen I secretion but had no effect on αSMA expression. In vivo, myocardial infarction resulted in a rapid increase in the numbers of αSMA-positive cardiac stromal cells by day 5 followed by a gradual decline. Genetic deletion of A2B receptors had no effect on the initial accumulation of αSMA-expressing stromal cells but hastened their subsequent decline; the numbers of αSMA-positive cells including Sca1(+)CD31(-) cells remained significantly higher in wild type compared with A2B knockout hearts. Thus, our study revealed a significant contribution of cardiac Sca1(+)CD31(-) cells to the accumulation of αSMA-expressing cells after infarction and implicated A2B receptor signaling in regulation of myocardial repair and remodeling by delaying deactivation of these cells. It is plausible that this phenomenon may contribute to the beneficial effects of transplantation of these cells to the injured heart.
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14
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Haghikia A, Ricke-Hoch M, Stapel B, Gorst I, Hilfiker-Kleiner D. STAT3, a key regulator of cell-to-cell communication in the heart. Cardiovasc Res 2014; 102:281-9. [PMID: 24518140 DOI: 10.1093/cvr/cvu034] [Citation(s) in RCA: 93] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
The signal transducer and activator of transcription 3 (STAT3) is fundamental for physiological homeostasis and stress-induced remodelling of the heart as deregulated STAT3 circuits are sufficient to induce dilated and peripartum cardiomyopathy and adverse remodelling after myocardial infarction. STAT3 activity depends on multiple post-translational modifications (phosphorylation, acetylation, and dimerization). It is regulated by multiple receptor systems, which are coupled to positive and negative feedback loops to ensure physiological and beneficial action. Its intracellular functions are diverse as it acts as a signalling protein, a transcription factor but also participates in mitochondria energy production and protection. STAT3 modulates proliferation, differentiation, survival, oxidative stress, and/or metabolism in cardiomyocytes, fibroblasts, endothelial cells, progenitor cells, and various inflammatory cells. By regulating the secretome of these cardiac cells, STAT3 influences a broad range of intercellular communication systems. It thereby impacts on the communication between cardiomyocytes, the plasticity of the cardiac microenvironment, the vasculature, the extracellular matrix, and the inflammation in response to physiological and pathophysiological stress. Here, we sum up current knowledge on STAT3-mediated intra- and intercellular communication within the heterogeneous cellular network of the myocardium to co-ordinate complex biological processes and discuss STAT3-dependent targets as novel therapeutic concepts to treat various forms of heart disease.
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Affiliation(s)
- Arash Haghikia
- Department of Cardiology and Angiology, Hannover Medical School, Carl-Neuberg Str. 1, 30625 Hannover, Germany
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15
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Abstract
Myocardial infarction leads to loss of cardiomyocytes, scar formation, ventricular remodeling and eventually deterioration of heart function. Over the past decade, stem cell therapy has emerged as a novel strategy for patients with ischemic heart disease and its beneficial effects have been demonstrated by substantial preclinical and clinical studies. Efficacy of several types of stem cells in the therapy of cardiovascular diseases has already been evaluated. However, repair of injured myocardium through stem cell transplantation is restricted by critical safety issues and ethic concerns. Recently, the discovery of cardiac stem cells (CSCs) that reside in the heart itself brings new prospects for myocardial regeneration and reconstitution of cardiac tissues. CSCs are positive for various stem cell markers and have the potential of self-renewal and multilineage differentiation. They play a pivotal role in the maintenance of heart homeostasis and cardiac repair. Elucidation of their biological characteristics and functions they exert in myocardial infarction are very crucial to further investigations on them. This review will focus on the field of cardiac stem cells and discuss technical and practical issues that may involve in their clinical applications in myocardial infarction.
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16
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Abstract
Multiple studies have shown that the cytokine leukemia inhibitory factor (LIF) is protective of the myocardium in the acute stress of ischemia-reperfusion. All three major intracellular signaling pathways that are activated by LIF in cardiac myocytes have been linked to actions that protect against oxidative stress and cell death, either at the level of the mitochondrion or via nuclear transcription. In addition, LIF has been shown to contribute to post-myocardial infarction cardiac repair and regeneration, by stimulating the homing of bone marrow-derived cardiac progenitors to the injured myocardium, the differentiation of resident cardiac stem cells into endothelial cells, and neovascularization. Whether LIF offers protection to the heart under chronic stress such as hypertension-induced cardiac remodeling and heart failure is not known. However, mice with cardiac myocyte restricted knockout of STAT3, a principal transcription factor activated by LIF, develop heart failure with age, and cardiac STAT3 levels are reported to be decreased in heart failure patients. In addition, endogenously produced LIF has been implicated in the cholinergic transdiffrentiation that may serve to attenuate sympathetic overdrive in heart failure and in the peri-infarct region of the heart after myocardial infarction. Surprisingly, therapeutic strategies to exploit the beneficial actions of LIF on the injured myocardium have received scant attention. Nor is it established whether the purported so-called adverse effects of LIF observed in isolated cardiac myocytes have physiological relevance in vivo. Here we present an overview of the actions of LIF in the heart with the goal of stimulating further research into the translational potential of this pleiotropic cytokine.
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17
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Ryzhov S, Zhang Q, Biaggioni I, Feoktistov I. Adenosine A2B receptors on cardiac stem cell antigen (Sca)-1-positive stromal cells play a protective role in myocardial infarction. THE AMERICAN JOURNAL OF PATHOLOGY 2013; 183:665-72. [PMID: 23827818 DOI: 10.1016/j.ajpath.2013.05.012] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/27/2012] [Revised: 05/03/2013] [Accepted: 05/20/2013] [Indexed: 01/14/2023]
Abstract
Transplantation of mesenchymal stem-like cells to the heart is known to improve cardiac recovery in animal models of myocardial infarction (MI). Because stimulation of A2B adenosine receptors on mouse cardiac stem cell antigen (Sca)-1(+)CD31(-) mesenchymal stem-like cells significantly up-regulates their secretion of pro-angiogenic factors, we hypothesized that ablation of the A2B receptor signaling in these cells would reduce their ability to improve vascularization of the infarct area seen after transplantation. Wild-type (WT) C57BL/6 mice underwent permanent left coronary artery ligation and received intramyocardial injections of Sca-1(+)CD31(-) cells generated from WT or A2B receptor knockout (A2BKO) mice or the same volume of cell-free saline. Only 12% to 16% of injected cells remained in the ventricles 1 week later; there was no significant difference between WT and A2BKO cell survival. Transplantation of WT, but not A2BKO, cells significantly reduced both post-MI decline in cardiac function and adverse remodeling compared with that seen in control hearts. Morphological analysis conducted 4 weeks after MI revealed significantly increased vascularization of the infarct areas and reduced myocardial scarring in animals treated with WT, but not with A2BKO, cells compared with control. Thus, our study demonstrated that the A2B receptor signaling linked to up-regulation of pro-angiogenic factors in cardiac Sca-1(+)CD31(-) stromal cells is essential for overall improvement of cardiac recovery seen after their transplantation to the injured heart.
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Affiliation(s)
- Sergey Ryzhov
- Division of Cardiovascular Medicine, Vanderbilt University Medical School, Nashville, Tennessee, USA
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18
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Wen Z, Mai Z, Zhang H, Chen Y, Geng D, Zhou S, Wang J. Local activation of cardiac stem cells for post-myocardial infarction cardiac repair. J Cell Mol Med 2012; 16:2549-63. [PMID: 22613044 PMCID: PMC4118225 DOI: 10.1111/j.1582-4934.2012.01589.x] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2012] [Accepted: 05/08/2012] [Indexed: 12/23/2022] Open
Abstract
The prognosis of patients with myocardial infarction (MI) and resultant chronic heart failure remains extremely poor despite continuous advancements in optimal medical therapy and interventional procedures. Animal experiments and clinical trials using adult stem cell therapy following MI have shown a global improvement of myocardial function. The emergence of stem cell transplantation approaches has recently represented promising alternatives to stimulate myocardial regeneration. Regarding their tissue-specific properties, cardiac stem cells (CSCs) residing within the heart have advantages over other stem cell types to be the best cell source for cell transplantation. However, time-consuming and costly procedures to expanse cells prior to cell transplantation and the reliability of cell culture and expansion may both be major obstacles in the clinical application of CSC-based transplantation therapy after MI. The recognition that the adult heart possesses endogenous CSCs that can regenerate cardiomyocytes and vascular cells has raised the unique therapeutic strategy to reconstitute dead myocardium via activating these cells post-MI. Several strategies, such as growth factors, mircoRNAs and drugs, may be implemented to potentiate endogenous CSCs to repair infarcted heart without cell transplantation. Most molecular and cellular mechanism involved in the process of CSC-based endogenous regeneration after MI is far from understanding. This article reviews current knowledge opening up the possibilities of cardiac repair through CSCs activation in situ in the setting of MI.
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Affiliation(s)
- Zhuzhi Wen
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Zun Mai
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Haifeng Zhang
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Yangxin Chen
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Dengfeng Geng
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Shuxian Zhou
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
| | - Jingfeng Wang
- Sun Yat-sen Memorial Hospital of Sun Yat-sen UniversityGuangzhou, China
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19
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Ryzhov S, Goldstein AE, Novitskiy SV, Blackburn MR, Biaggioni I, Feoktistov I. Role of A2B adenosine receptors in regulation of paracrine functions of stem cell antigen 1-positive cardiac stromal cells. J Pharmacol Exp Ther 2012; 341:764-74. [PMID: 22431204 PMCID: PMC3362889 DOI: 10.1124/jpet.111.190835] [Citation(s) in RCA: 25] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2011] [Accepted: 03/12/2012] [Indexed: 01/29/2023] Open
Abstract
The existence of multipotent cardiac stromal cells expressing stem cell antigen (Sca)-1 has been reported, and their proangiogenic properties have been demonstrated in myocardial infarction models. In this study, we tested the hypothesis that stimulation of adenosine receptors on cardiac Sca-1(+) cells up-regulates their secretion of proangiogenic factors. We found that Sca-1 is expressed in subsets of mouse cardiac stromal CD31(-) and endothelial CD31(+) cells. The population of Sca-1(+)CD31(+) endothelial cells was significantly reduced, whereas the population of Sca-1(+)CD31(-) stromal cells was increased 1 week after myocardial infarction, indicating their relative functional importance in this pathophysiological process. An increase in adenosine levels in adenosine deaminase-deficient mice in vivo significantly augmented vascular endothelial growth factor (VEGF) production in cardiac Sca-1(+)CD31(-) stromal cells but not in Sca-1(+)CD31(+) endothelial cells. We found that mouse cardiac Sca-1(+)CD31(-) stromal cells predominantly express mRNA encoding A(2B) adenosine receptors. Stimulation of adenosine receptors significantly increased interleukin (IL)-6, CXCL1 (a mouse ortholog of human IL-8), and VEGF release from these cells. Using conditionally immortalized Sca-1(+)CD31(-) stromal cells obtained from wild-type and A(2B) receptor knockout mouse hearts, we demonstrated that A(2B) receptors are essential for adenosine-dependent up-regulation of their paracrine functions. We found that the human heart also harbors a population of stromal cells similar to the mouse cardiac Sca-1(+)CD31(-) stromal cells that increase release of IL-6, IL-8, and VEGF in response to A(2B) receptor stimulation. Thus, our study identified A(2B) adenosine receptors on cardiac stromal cells as potential targets for up-regulation of proangiogenic factors in the ischemic heart.
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Affiliation(s)
- Sergey Ryzhov
- Division of Cardiovascular Medicine, and Department of Medicine, Vanderbilt University Medical School, Nashville, Tennessee 37232, USA
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20
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Hoch M, Fischer P, Stapel B, Missol-Kolka E, Sekkali B, Scherr M, Favret F, Braun T, Eder M, Schuster-Gossler K, Gossler A, Hilfiker A, Balligand JL, Drexler H, Hilfiker-Kleiner D. Erythropoietin preserves the endothelial differentiation capacity of cardiac progenitor cells and reduces heart failure during anticancer therapies. Cell Stem Cell 2012; 9:131-43. [PMID: 21816364 DOI: 10.1016/j.stem.2011.07.001] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2010] [Revised: 05/31/2011] [Accepted: 07/05/2011] [Indexed: 11/17/2022]
Abstract
Anticancer therapies, such as targeting of STAT3 or the use of anthracyclins (doxorubicin), can induce cardiomyopathy. In mice prone to developing heart failure as a result of reduced cardiac STAT3 expression (cardiomyocyte-restricted deficiency of STAT3) or treatment with doxorubicin, we observed impaired endothelial differentiation capacity of Sca-1(+) cardiac progenitor cells (CPCs) in conjunction with attenuated CCL2/CCR2 activation. Mice in both models also displayed reduced erythropoietin (EPO) levels in the cardiac microenvironment. EPO binds to CPCs and seems to be responsible for maintaining an active CCL2/CCR2 system. Supplementation with the EPO derivative CERA in a hematocrit-inactive low dose was sufficient to upregulate CCL2, restore endothelial differentiation of CPCs, and preserve the cardiac microvasculature and cardiac function in both mouse models. Thus, low-dose EPO treatment could potentially be exploited as a therapeutic strategy to reduce the risk of heart failure in certain treatment regimens.
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Affiliation(s)
- Melanie Hoch
- Department of Cardiology and Angiology, Medical School Hannover, 30625 Hannover, Germany
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Fujio Y, Maeda M, Mohri T, Obana M, Iwakura T, Hayama A, Yamashita T, Nakayama H, Azuma J. Glycoprotein 130 cytokine signal as a therapeutic target against cardiovascular diseases. J Pharmacol Sci 2011; 117:213-22. [PMID: 22056652 DOI: 10.1254/jphs.11r05cr] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/15/2022] Open
Abstract
Postnatal cardiomyocytes have only limited capacity of proliferation. Therefore, the myocardium is intrinsically equipped with cardioprotective machineries and protects itself from pathological stresses. One of the most important cardioprotective systems is the signal network of autocrine/paracrine factors, including neurohumoral factors, growth factors, and cytokines. In this review, we focus on the roles of interleukin-6 (IL-6) family cytokines, also known as glycoprotein 130 (gp130) cytokines, in cardioprotection. These cytokines make a complex with their specific cytokine receptor α-subunits. The cytokine-receptor α-subunit complex binds to gp130, a common receptor of the IL-6 family, followed by the activation of JAK/STAT, ERK, and PI3 kinase/Akt pathways. In cardiomyocytes, signals through gp130 promote cell survival and angiogenesis through the JAK/STAT pathway. Activation of gp130 in cardiac stem cells induces their endothelial transdifferentiation, leading to neovascularization. Recently, accumulating evidence has revealed that altered JAK/STAT activity is associated with heart failure, suggesting that the JAK/STAT pathway is a therapeutic target against cardiovascular diseases. Interestingly, activation of the JAK/STAT pathway with interleukin-11 (IL-11) exhibits preconditioning effects in ischemia/reperfusion model. Moreover, IL-11 treatment after coronary ligation prevents cardiac remodeling through the JAK/STAT pathway. Since IL-11 is used for patients with thrombocytopenia, we propose that IL-11 is a candidate cytokine clinically available for cardioprotection therapy.
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Affiliation(s)
- Yasushi Fujio
- Laboratory of Clinical Science and Biomedicine, Graduate School of Pharmaceutical Sciences, Osaka University, Japan.
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22
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Iwakura T, Mohri T, Hamatani T, Obana M, Yamashita T, Maeda M, Katakami N, Kaneto H, Oka T, Komuro I, Azuma J, Nakayama H, Fujio Y. STAT3/Pim-1 signaling pathway plays a crucial role in endothelial differentiation of cardiac resident Sca-1+ cells both in vitro and in vivo. J Mol Cell Cardiol 2011; 51:207-14. [PMID: 21600215 DOI: 10.1016/j.yjmcc.2011.04.013] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/07/2010] [Revised: 02/18/2011] [Accepted: 04/28/2011] [Indexed: 11/26/2022]
Abstract
Cardiac stem cells potentially differentiate into cardiac cells, including cardiomyocytes and endothelial cells (ECs). Previously we demonstrated that STAT3 activation by IL-6 family cytokines, such as leukemia inhibitory factor (LIF), induces the endothelial differentiation of cardiac Sca-1+ cells. In this study, we addressed molecular mechanisms for EC differentiation of Sca-1+ cells. First, DNA array experiments were performed to search for the molecules induced by LIF. Among 134 genes that LIF upregulated by more than 4 fold, we focused on Pim-1 gene transcript, because Pim-1 is associated with the differentiation of some cell lineages. Real time RT-PCR analyses confirmed that LIF stimulation upregulated Pim-1 expression. Adenoviral transfection of dominant negative (dn) STAT3 inhibited LIF-mediated induction of Pim-1, while the overexpression of constitutively active STAT3 upregulated Pim-1 expression, suggesting that STAT3 activation is necessary and sufficient for Pim-1 induction. Moreover, in STAT3-deficient Sca-1+ cells, LIF failed to induce Pim-1 expression and EC differentiation. Importantly, the overexpression of dnPim-1 abrogated the induction of EC markers, indicating Pim kinase activity is indispensable for STAT3-mediated EC differentiation in vitro. Finally, Sca-1+ cells labeled with LacZ were transplanted into post-infarct myocardium and the transdifferentiation was estimated. The overexpression of wild-type STAT3 by adenovirus vector significantly promoted EC differentiation, while STAT3 gene ablation reduced the frequency of differentiating cells in post-infarct myocardium. Furthermore, transplanted Sca-1+ cells overexpressing dnPim-1 showed the reduced frequency of EC differentiation and capillary density. Collectively, Pim-1 kinase is upregulated by STAT3 activation in cardiac Sca-1+ cells and plays a pivotal role in EC differentiation both in vitro and in vivo.
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Affiliation(s)
- Tomohiko Iwakura
- Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka Suita City, 565-0871, Osaka, Japan
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Abstract
Cardiotrophin (CT)-1 was discovered by coupling expression cloning with an embryonic stem cell-based model of cardiogenesis. Comparison of similarity in amino acid sequence and conformational structure indicates that CT-1 is a member of the interleukin (IL)-6 type cytokine family that shares the transmembrane signaling protein, glycoprotein (gp) 130 as a receptor. These cytokines mediate overlapping pleiotropic actions on a variety of cell types including cardiac myocytes, hepatocytes, megakaryocytes, osteoclasts, and neuronal cells. CT-lmediates its hypertrophic and cytoprotective properties through the Janus kinase/signal transducers and activators of transcription (JAK/STAT), mitogen-activated protein (MAP) kinase, phosphatidylinositol (PI) 3 kinase, and nuclear factor kappa B (NFkappaB) pathways. CT-1 gene and protein are distributed not only in the heart, but also in the pulmonary, renal, gastrointestinal, cerebral, and muscular tissues. CT-1 could also be synthesized and secreted from vascular endothelial cells and adipocytes. CT-1 has hypertrophic actions on the cardiac myocytes, skeletal muscle cells, and smooth muscle cells as well as cytoprotective actions on the cardiac myocytes, neuronal cells, and hepatocytes. CT-1 is circulating in the body, and its plasma concentration is increased in various cardiovascular and renal diseases such as hypertension, congestive heart failure, myocardial infarction, valvular heart disease, metabolic syndrome, and chronic kidney disease. Treatment with CT-1 is beneficial in experimental animal models of cardiovascular diseases. CT-1 specifically protects the cardiac myocytes from ischemic damage when CT-1 is given not only prior to the ischemia, but also given at the time of reoxygenation. Current evidence suggests that CT-1 plays an important role in the regulation of the cardiovascular system.
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Affiliation(s)
- Michihisa Jougasaki
- Institute for Clinical Research, National Hospital Organization Kagoshima Medical Center, Kagoshima, Japan.
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Washio I, Maeda M, Sugiura C, Shiga R, Yoshida M, Nonen S, Fujio Y, Azuma J. Cigarette smoke extract induces CYP2B6 through constitutive androstane receptor in hepatocytes. Drug Metab Dispos 2011; 39:1-3. [PMID: 20966044 DOI: 10.1124/dmd.110.034504] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2023] Open
Abstract
Smoking induces a wide range of drug-metabolizing enzymes. Among them, CYP2B6 as well as CYP1A2 is well known to be up-regulated in smokers. Although the induction of CYP1A2 is mediated by the aryl hydrocarbon receptor, the molecular mechanisms of CYP2B6 induction by smoking remain to be fully elucidated. In this study, by preparing cigarette smoke extract (CSE), we addressed the possibility that human constitutive androstane receptor (hCAR) is involved in smoking-mediated induction of CYP2B6. In HepG2 cells, CSE induced CYP1A2 but not CYP2B6, suggesting that CYP2B6 expression is differentially regulated from CYP1A2. Compared with liver in vivo, hCAR expression is dramatically reduced in cultured hepatocytes, such as HepG2. Therefore, to reconstitute hCAR signaling pathways in vitro, we generated adenovirus vector expressing hCAR. Real-time reverse transcription-polymerase chain reaction analyses revealed that the adenoviral transfection of hCAR resulted in the up-regulation of CYP2B6 mRNA, even in the absence of CSE. It is interesting to note that CSE stimulation augmented hCAR-mediated induction of CYP2B6. In contrast, the expression of CYP2B6 was not enhanced by adenovirus vector expressing β-galactosidase, a control vector, either in the presence or absence of CSE. In summary, hCAR mediated the CYP2B6 induction by CSE in Hep2G cells. These data suggest that smoking up-regulates CYP2B6 through hCAR in vivo.
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Affiliation(s)
- Ikumi Washio
- Department of Clinical Pharmacology and Pharmacogenomics, Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan
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