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1
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Odontogenic Differentiation-Induced Tooth Regeneration by Psoralea corylifolia L. Curr Issues Mol Biol 2022; 44:2300-2308. [PMID: 35678685 PMCID: PMC9164060 DOI: 10.3390/cimb44050156] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 05/13/2022] [Accepted: 05/18/2022] [Indexed: 01/22/2023] Open
Abstract
Psoralea corylifolia L. (P. corylifolia) has been used as an oriental phytomedicine to treat coldness of hands and feet in bone marrow injury. Hydroxyapatite is usually used for tooth regeneration. In this study, the role of P. corylifolia and bakuchiol, a compound originated from P. corylifolia as differentiation-inducing substances for tooth regeneration, was determined by monitoring odontogenic differentiation in human dental pulp stem cells (hDPSCs). We confirmed that P. corylifolia extracts and bakuchiol increased the odontogenic differentiation of hDPSCs. In addition, the expression of the odontogenic differentiation marker genes alkaline phosphatase (APL), Runt-related transcription factor 2 (RUNX-2), osteocalcin (OC), and dentin matrix acidic phosphoprotein-1 (DMP-1) was proved by real-time polymerase chain reaction, and protein expression of dentin matrix acidic phosphoprotein-1 (DMP-1) and dentin sialophosphoprotein (DSPP) was proved by western blotting. Further, by confirming the increase in small mothers against decapentaplegia (SMAD) 1/5/8 phosphorylation, the SMAD signaling pathway was found to increase the differentiation of odontoblasts. This study confirmed that P. corylifolia L. extracts and bakuchiol alone promote odontogenic differentiation in hDPSCs. These results suggest that bakuchiol from P. corylifolia is responsible for odontogenic differentiation, and they encourage future in vivo studies on dentin regeneration.
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2
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Chumachenko MS, Waseem TV, Fedorovich SV. Metabolomics and metabolites in ischemic stroke. Rev Neurosci 2021; 33:181-205. [PMID: 34213842 DOI: 10.1515/revneuro-2021-0048] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2021] [Accepted: 06/09/2021] [Indexed: 12/27/2022]
Abstract
Stroke is a major reason for disability and the second highest cause of death in the world. When a patient is admitted to a hospital, it is necessary to identify the type of stroke, and the likelihood for development of a recurrent stroke, vascular dementia, and depression. These factors could be determined using different biomarkers. Metabolomics is a very promising strategy for identification of biomarkers. The advantage of metabolomics, in contrast to other analytical techniques, resides in providing low molecular weight metabolite profiles, rather than individual molecule profiles. Technically, this approach is based on mass spectrometry and nuclear magnetic resonance. Furthermore, variations in metabolite concentrations during brain ischemia could alter the principal neuronal functions. Different markers associated with ischemic stroke in the brain have been identified including those contributing to risk, acute onset, and severity of this pathology. In the brain, experimental studies using the ischemia/reperfusion model (IRI) have shown an impaired energy and amino acid metabolism and confirmed their principal roles. Literature data provide a good basis for identifying markers of ischemic stroke and hemorrhagic stroke and understanding metabolic mechanisms of these diseases. This opens an avenue for the successful use of identified markers along with metabolomics technologies to develop fast and reliable diagnostic tools for ischemic and hemorrhagic stroke.
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Affiliation(s)
- Maria S Chumachenko
- Department of Biochemistry, Faculty of Biology, Belarusian State University, Kurchatova St., 10, Minsk220030, Belarus
| | | | - Sergei V Fedorovich
- Department of Biochemistry, Faculty of Biology, Belarusian State University, Kurchatova St., 10, Minsk220030, Belarus
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3
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Shi W, Xin Q, Yuan R, Yuan Y, Cong W, Chen K. Neovascularization: The Main Mechanism of MSCs in Ischemic Heart Disease Therapy. Front Cardiovasc Med 2021; 8:633300. [PMID: 33575274 PMCID: PMC7870695 DOI: 10.3389/fcvm.2021.633300] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2020] [Accepted: 01/05/2021] [Indexed: 12/17/2022] Open
Abstract
Mesenchymal stem cell (MSC) transplantation after myocardial infarction (MI) has been shown to effectively limit the infarct area in numerous clinical and preclinical studies. However, the primary mechanism associated with this activity in MSC transplantation therapy remains unclear. Blood supply is fundamental for the survival of myocardial tissue, and the formation of an efficient vascular network is a prerequisite for blood flow. The paracrine function of MSCs, which is throughout the neovascularization process, including MSC mobilization, migration, homing, adhesion and retention, regulates angiogenesis and vasculogenesis through existing endothelial cells (ECs) and endothelial progenitor cells (EPCs). Additionally, MSCs have the ability to differentiate into multiple cell lineages and can be mobilized and migrate to ischemic tissue to differentiate into ECs, pericytes and smooth muscle cells in some degree, which are necessary components of blood vessels. These characteristics of MSCs support the view that these cells improve ischemic myocardium through angiogenesis and vasculogenesis. In this review, the results of recent clinical and preclinical studies are discussed to illustrate the processes and mechanisms of neovascularization in ischemic heart disease.
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Affiliation(s)
- Weili Shi
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Qiqi Xin
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Rong Yuan
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Yahui Yuan
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Weihong Cong
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
| | - Keji Chen
- Laboratory of Cardiovascular Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China.,National Clinical Research Center for Chinese Medicine Cardiology, Beijing, China
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4
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Maslovaric M, Fatic N, Delević E. State of the art of stem cell therapy for ischaemic cardiomyopathy. Part 2. ANGIOLOGII︠A︡ I SOSUDISTAI︠A︡ KHIRURGII︠A︡ = ANGIOLOGY AND VASCULAR SURGERY 2020; 25:7-26. [PMID: 31855197 DOI: 10.33529/angio2019414] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
Ischemic cardiomyopathy is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ischemic cardiomyopathy. Several stem cell types, including cardiac-derived stem cells, bone marrow-derived stem cells, mesenchymal stem cells, skeletal myoblasts, CD34+ and CD133+ stem cells have been used in clinical trials. Clinical effects mostly depend on transdifferentiation and paracrine factors. One important issue is that a low survival and residential rate of transferred stem cells blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ischemic cardiomyopathy mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical conditions, the particular microenvironment onto which the cells are delivered, and clinical conditions remain to be addressed. Here we provide an overview of modern methods of stem cell delivery, types of stem cells and discuss the current state of their therapeutic potential.
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Affiliation(s)
- Milica Maslovaric
- Prona-Montenegrin Science Promotion Foundation, Podgorica, Montenegro
| | - Nikola Fatic
- Department of Vascular Surgery, Clinical Centre of Montenegro, Podgorica, Montenegro
| | - Emilija Delević
- Medical Faculty in Podgorica, University of Montenegro, Podgorica, Montenegro
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5
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Ju X, Xue D, Wang T, Ge B, Zhang Y, Li Z. Catalpol Promotes the Survival and VEGF Secretion of Bone Marrow-Derived Stem Cells and Their Role in Myocardial Repair After Myocardial Infarction in Rats. Cardiovasc Toxicol 2019; 18:471-481. [PMID: 29752623 DOI: 10.1007/s12012-018-9460-4] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Bone mesenchymal stem cells (BMSCs) transplantation has been recognized as an effective method for the treatment of myocardial infarction (MI). However, its efficacy is always restricted by the low survival of transplanted BMSCs in the ischemic myocardium. The aim of this study was to investigate the effect of catalpol pre-treatment on the survival and vascular endothelial growth factor (VEGF) secretion of BMSCs under oxygen glucose deprivation (OGD) condition and their role in myocardial repair in a rat model of MI. According to our results, pre-treatment with catalpol enhanced VEGF secretion and survival of OGD-treated BMSCs. Moreover, the apoptosis of BMSCs induced by OGD was restrained by catalpol as evidenced by increased level of B-cell lymphoma-2 (Bcl-2) and decreased levels of BCL2-associated X (Bax) and cleaved caspase-3. In vivo study suggested that the survival of transplanted BMSCs was improved by catalpol pre-treatment. The myocardial fibrosis and apoptosis was further inhibited in catalpol pre-treated BMSCs group. Cardiac function detected by echocardiography was obviously improved by catalpol pre-treated BMSCs transplantation. Finally, angiogenesis and VEGF expression in the ischemic myocardium were significantly promoted in catalpol pre-treated BMSCs group. In conclusion, catalpol pre-treatment may facilitate the survival and VEGF secretion of BMSCs and improve their therapeutic effect on MI.
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Affiliation(s)
- Xing'ai Ju
- Department of Cardiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China.,Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Degang Xue
- Comprehensive Circulation Ward, The General Hospital of Fushun Mining Affairs Bureau, Fushun, 113008, Liaoning, People's Republic of China
| | - Tongyi Wang
- Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Baiping Ge
- Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Yu Zhang
- Department of Emergency Medicine, The People's Hospital of Liaoning Province, Shenyang, 110016, Liaoning, People's Republic of China
| | - Zhanquan Li
- Department of Cardiology, Shengjing Hospital of China Medical University, 36 Sanhao Street, Shenyang, 110004, Liaoning, People's Republic of China.
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6
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Lidgerwood GE, Pitson SM, Bonder C, Pébay A. Roles of lysophosphatidic acid and sphingosine-1-phosphate in stem cell biology. Prog Lipid Res 2018; 72:42-54. [PMID: 30196008 DOI: 10.1016/j.plipres.2018.09.001] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2018] [Revised: 08/15/2018] [Accepted: 09/05/2018] [Indexed: 02/06/2023]
Abstract
Stem cells are unique in their ability to self-renew and differentiate into various cell types. Because of these features, stem cells are key to the formation of organisms and play fundamental roles in tissue regeneration and repair. Mechanisms controlling their fate are thus fundamental to the development and homeostasis of tissues and organs. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are bioactive phospholipids that play a wide range of roles in multiple cell types, during developmental and pathophysiological events. Considerable evidence now demonstrates the potent roles of LPA and S1P in the biology of pluripotent and adult stem cells, from maintenance to repair. Here we review their roles for each main category of stem cells and explore how those effects impact development and physiopathology.
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Affiliation(s)
- Grace E Lidgerwood
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia
| | - Stuart M Pitson
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Claudine Bonder
- Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, Australia
| | - Alice Pébay
- Centre for Eye Research Australia, Royal Victorian Eye and Ear Hospital, East Melbourne, Australia; Ophthalmology, Department of Surgery, the University of Melbourne, Melbourne, Australia.
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7
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D'Souza K, Paramel GV, Kienesberger PC. Lysophosphatidic Acid Signaling in Obesity and Insulin Resistance. Nutrients 2018; 10:nu10040399. [PMID: 29570618 PMCID: PMC5946184 DOI: 10.3390/nu10040399] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Revised: 03/13/2018] [Accepted: 03/20/2018] [Indexed: 12/21/2022] Open
Abstract
Although simple in structure, lysophosphatidic acid (LPA) is a potent bioactive lipid that profoundly influences cellular signaling and function upon binding to G protein-coupled receptors (LPA1-6). The majority of circulating LPA is produced by the secreted enzyme autotaxin (ATX). Alterations in LPA signaling, in conjunction with changes in autotaxin (ATX) expression and activity, have been implicated in metabolic and inflammatory disorders including obesity, insulin resistance, and cardiovascular disease. This review summarizes our current understanding of the sources and metabolism of LPA with focus on the influence of diet on circulating LPA. Furthermore, we explore how the ATX-LPA pathway impacts obesity and obesity-associated disorders, including impaired glucose homeostasis, insulin resistance, and cardiovascular disease.
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Affiliation(s)
- Kenneth D'Souza
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5 Canada.
| | - Geena V Paramel
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5 Canada.
| | - Petra C Kienesberger
- Department of Biochemistry and Molecular Biology, Faculty of Medicine, Dalhousie University, Dalhousie Medicine New Brunswick, Saint John, NB, E2L 4L5 Canada.
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8
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Mo WM, Kwon YW, Jang IH, Choi EJ, Kwon SM, Kim JH. Role of TAZ in Lysophosphatidic Acid-Induced Migration and Proliferation of Human Adipose-Derived Mesenchymal Stem Cells. Biomol Ther (Seoul) 2017; 25:354-361. [PMID: 28554198 PMCID: PMC5499612 DOI: 10.4062/biomolther.2016.263] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2016] [Revised: 02/28/2017] [Accepted: 02/28/2017] [Indexed: 12/15/2022] Open
Abstract
Transcriptional co-activator with a PDZ-binding motif (TAZ) is an important factor in lysophosphatidic acid (LPA)-induced promotion of migration and proliferation of human mesenchymal stem cells (MSCs). The expression of TAZ significantly increased at 6 h after LPA treatment, and TAZ knockdown inhibited the LPA-induced migration and proliferation of MSCs. In addition, embryonic fibroblasts from TAZ knockout mice exhibited the reduction in LPA-induced migration and proliferation. The LPA1 receptor inhibitor Ki16425 blocked LPA responses in MSCs. Although TAZ knockdown or knockout did not reduce LPA-induced phosphorylation of ERK and AKT, the MEK inhibitor U0126 or the ROCK inhibitor Y27632 blocked LPA-induced TAZ expression along with the reduction in the proliferation and migration of MSCs. Our data suggest that TAZ is an important mediator of LPA signaling in MSCs in the downstream of MEK and ROCK signaling.
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Affiliation(s)
- Won Min Mo
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Yang Woo Kwon
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Il Ho Jang
- Department of Oral Biochemistry and Molecular Biology, Pusan National University School of Dentistry, Yangsan 50612, Republic of Korea.,BK21 PLUS Project, Pusan National University School of Dentistry, Yangsan 50612, Republic of Korea
| | - Eun Jung Choi
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Sang Mo Kwon
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea
| | - Jae Ho Kim
- Department of Physiology, Pusan National University School of Medicine, Yangsan 50612, Republic of Korea.,Research Institute of Convergence Biomedical Science and Technology, Pusan National University Yangsan Hospital, Yangsan 50612, Republic of Korea
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9
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Purroy F, Cambray S, Mauri-Capdevila G, Jové M, Sanahuja J, Farré J, Benabdelhak I, Molina-Seguin J, Colàs-Campàs L, Begue R, Gil MI, Pamplona R, Portero-Otín M. Metabolomics Predicts Neuroimaging Characteristics of Transient Ischemic Attack Patients. EBioMedicine 2016; 14:131-138. [PMID: 27843094 PMCID: PMC5161417 DOI: 10.1016/j.ebiom.2016.11.010] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Revised: 11/06/2016] [Accepted: 11/07/2016] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND Neuroimaging is essential for the diagnosis and prognosis of transient ischemic attack (TIA). The discovery of a plasmatic biomarker related to neuroimaging findings is of enormous interest because, despite its relevance, magnetic resonance diffusion weighted imaging (DWI) is not always available in all hospitals that attend to TIA patients. METHODS Metabolomic analyses were performed by liquid chromatography coupled to mass spectrometry in order to establish the metabolomic patterns of positive DWI, DWI patterns and acute ischemic lesion volumes. We used these methods with an initial TIA cohort of 129 patients and validated them with a 2nd independent cohort of 152 patients. FINDINGS Positive DWI was observed in 115 (40.9%) subjects and scattered pearls in one arterial territory was the most frequent lesion pattern (35.7%). The median acute ischemic lesion volume was 0.33 (0.15-1.90)cm3. We detected a specific metabolomic profile common to both cohorts for positive DWI (11 molecules including creatinine, threoninyl-threonine, N-acetyl-glucosamine, lyso phosphatidic acid and cholesterol-related molecules) and ischemic lesion volume (10 molecules including lysophosphatidylcholine, hypoxanthine/threonate, and leucines). Moreover lysophospholipids and creatinine clearly differed the subcortical DWI pattern from other patterns. INTERPRETATION There are specific metabolomic profiles associated with representative neuroimaging features in TIA patients. Our findings could allow the development of serum biomarkers related to acute ischemic lesions and specific acute ischemic patterns.
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Affiliation(s)
- Francisco Purroy
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain.
| | - Serafi Cambray
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Gerard Mauri-Capdevila
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Mariona Jové
- NUTREN-Nutrigenomics Center, Department of Experimental Medicine, Parc Científic i Tecnològic Agroalimentari de Lleida-Universitat de Lleida-IRBLLEIDA, Lleida, Spain
| | - Jordi Sanahuja
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Joan Farré
- Laboratori Clinic, Universitari Arnau de Vilanova de Lleida, Clinical Neurosciences Group IRBLleida, Spain
| | - Ikram Benabdelhak
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Jessica Molina-Seguin
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Laura Colàs-Campàs
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Robert Begue
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - M Isabel Gil
- Stroke Unit, Department of Neurology, Universitat de Lleida, Hospital Universitari Arnau de Vilanova de Leida, Clinical Neurosciences Group IRBLleida, Spain
| | - Reinald Pamplona
- NUTREN-Nutrigenomics Center, Department of Experimental Medicine, Parc Científic i Tecnològic Agroalimentari de Lleida-Universitat de Lleida-IRBLLEIDA, Lleida, Spain
| | - Manuel Portero-Otín
- NUTREN-Nutrigenomics Center, Department of Experimental Medicine, Parc Científic i Tecnològic Agroalimentari de Lleida-Universitat de Lleida-IRBLLEIDA, Lleida, Spain
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10
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Liu Y, Zhang H. Low-Level Laser Irradiation Precondition for Cardiac Regenerative Therapy. Photomed Laser Surg 2016; 34:572-579. [PMID: 27627137 DOI: 10.1089/pho.2015.4058] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
OBJECTIVE The purpose of this article was to review the molecular mechanisms of low-level laser irradiation (LLLI) preconditioning for heart cell therapy. BACKGROUND DATA Stem cell transplantation appears to offer a better alternative to cardiac regenerative therapy. Previous studies have confirmed that the application of LLLI plays a positive role in regulating stem cell proliferation and in remodeling the hostile milieu of infarcted myocardium. Greater understanding of LLLI's underlying mechanisms would be helpful in translating cell transplantation therapy into the clinic. METHODS Studies investigating LLLI preconditioning for cardiac regenerative therapy published up to 2015 were retrieved from library sources and Pubmed databases. RESULTS LLLI preconditioning stimulates proliferation and differentiation of stem cells through activation of cell proliferation signaling pathways and alteration of microRNA expression. It also could stimulate paracrine secretion of stem cells and alter cardiac cytokine expression in infarcted myocardium. CONCLUSIONS LLLI preconditioning provides a promising approach to maximize the efficacy of cardiac cell-based therapy. Although many studies have reported possible molecular mechanisms involved in LLLI preconditioning, the exact mechanisms are still not clearly understood.
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Affiliation(s)
- Yiwei Liu
- State Key Laboratory of Cardiovascular Disease and Key laboratory of Cardiac Regenerative Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, China
| | - Hao Zhang
- State Key Laboratory of Cardiovascular Disease and Key laboratory of Cardiac Regenerative Medicine, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College , Beijing, China
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11
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Lee HJ, Ryu JM, Jung YH, Lee KH, Kim DI, Han HJ. Glycerol-3-phosphate acyltransferase-1 upregulation by O-GlcNAcylation of Sp1 protects against hypoxia-induced mouse embryonic stem cell apoptosis via mTOR activation. Cell Death Dis 2016; 7:e2158. [PMID: 27010859 PMCID: PMC4823928 DOI: 10.1038/cddis.2015.410] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2015] [Revised: 12/10/2015] [Accepted: 12/14/2015] [Indexed: 12/20/2022]
Abstract
Oxygen signaling is critical for stem cell regulation, and oxidative stress-induced stem cell apoptosis decreases the efficiency of stem cell therapy. Hypoxia activates O-linked β-N-acetyl glucosaminylation (O-GlcNAcylation) of stem cells, which contributes to regulation of cellular metabolism, as well as cell fate. Our study investigated the role of O-GlcNAcylation via glucosamine in the protection of hypoxia-induced apoptosis of mouse embryonic stem cells (mESCs). Hypoxia increased mESCs apoptosis in a time-dependent manner. Moreover, hypoxia also slightly increased the O-GlcNAc level. Glucosamine treatment further enhanced the O-GlcNAc level and prevented hypoxia-induced mESC apoptosis, which was suppressed by O-GlcNAc transferase inhibitors. In addition, hypoxia regulated several lipid metabolic enzymes, whereas glucosamine increased expression of glycerol-3-phosphate acyltransferase-1 (GPAT1), a lipid metabolic enzyme producing lysophosphatidic acid (LPA). In addition, glucosamine-increased O-GlcNAcylation of Sp1, which subsequently leads to Sp1 nuclear translocation and GPAT1 expression. Silencing of GPAT1 by gpat1 siRNA transfection reduced glucosamine-mediated anti-apoptosis in mESCs and reduced mammalian target of rapamycin (mTOR) phosphorylation. Indeed, LPA prevented mESCs from undergoing hypoxia-induced apoptosis and increased phosphorylation of mTOR and its substrates (S6K1 and 4EBP1). Moreover, mTOR inactivation by rapamycin (mTOR inhibitor) increased pro-apoptotic proteins expressions and mESC apoptosis. Furthermore, transplantation of non-targeting siRNA and glucosamine-treated mESCs increased cell survival and inhibited flap necrosis in mouse skin flap model. Conversely, silencing of GPAT1 expression reversed those glucosamine effects. In conclusion, enhancing O-GlcNAcylation of Sp1 by glucosamine stimulates GPAT1 expression, which leads to inhibition of hypoxia-induced mESC apoptosis via mTOR activation.
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Affiliation(s)
- H J Lee
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 Creative Veterinary Research Center, Seoul National University, Seoul, Korea
| | - J M Ryu
- Department of Veterinary Physiology, College of Veterinary Medicine, Chonnam National University, Gwangju 61186, Korea
| | - Y H Jung
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 Creative Veterinary Research Center, Seoul National University, Seoul, Korea
| | - K H Lee
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 Creative Veterinary Research Center, Seoul National University, Seoul, Korea
| | - D I Kim
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 Creative Veterinary Research Center, Seoul National University, Seoul, Korea
| | - H J Han
- Department of Veterinary Physiology, College of Veterinary Medicine, Research Institute for Veterinary Science and BK21 Creative Veterinary Research Center, Seoul National University, Seoul, Korea
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12
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Lysophosphatidic acid enhances survival of human CD34(+) cells in ischemic conditions. Sci Rep 2015; 5:16406. [PMID: 26553339 PMCID: PMC4639756 DOI: 10.1038/srep16406] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2015] [Accepted: 09/07/2015] [Indexed: 01/05/2023] Open
Abstract
Several clinical trials are exploring therapeutic effect of human CD34+ cells in ischemic diseases, including myocardial infarction. Unfortunately, most of the cells die few days after delivery. Herein we show that lysophosphatidic acid (LPA)-treated human umbilical cord blood-derived CD34+ cells cultured under hypoxic and serum-deprived conditions present 2.2-fold and 1.3-fold higher survival relatively to non-treated cells and prostaglandin E2-treated cells, respectively. The pro-survival effect of LPA is concentration- and time-dependent and it is mediated by the activation of peroxisome proliferator-activator receptor γ (PPARγ) and downstream, by the activation of pro-survival ERK and Akt signaling pathways and the inhibition of mitochondrial apoptotic pathway. In hypoxia and serum-deprived culture conditions, LPA induces CD34+ cell proliferation without maintaining the their undifferentiating state, and enhances IL-8, IL-6 and G-CSF secretion during the first 12 h compared to non-treated cells. LPA-treated CD34+ cells delivered in fibrin gels have enhanced survival and improved cardiac fractional shortening at 2 weeks on rat infarcted hearts as compared to hearts treated with placebo. We have developed a new platform to enhance the survival of CD34+ cells using a natural and cost-effective ligand and demonstrated its utility in the preservation of the functionality of the heart after infarction.
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13
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Binder BYK, Williams PA, Silva EA, Leach JK. Lysophosphatidic Acid and Sphingosine-1-Phosphate: A Concise Review of Biological Function and Applications for Tissue Engineering. TISSUE ENGINEERING PART B-REVIEWS 2015; 21:531-42. [PMID: 26035484 DOI: 10.1089/ten.teb.2015.0107] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
The presentation and controlled release of bioactive signals to direct cellular growth and differentiation represents a widely used strategy in tissue engineering. Historically, work in this field has primarily focused on the delivery of large cytokines and growth factors, which can be costly to manufacture and difficult to deliver in a sustained manner. There has been a marked increase over the past decade in the pursuit of lipid mediators due to their wide range of effects over multiple cell types, low cost, and ease of scale-up. Lysophosphatidic acid (LPA) and sphingosine-1-phosphate (S1P) are two bioactive lysophospholipids (LPLs) that have gained attention for use as pharmacological agents in tissue engineering applications. While these lipids can have similar effects on cellular response, they possess distinct chemical backbones, mechanisms of synthesis and degradation, and signaling pathways using a discrete set of G-protein-coupled receptors (GPCRs). LPA and S1P predominantly act extracellularly on their GPCRs and can directly regulate cell survival, differentiation, cytokine secretion, proliferation, and migration--each of the important functions that must be considered in regenerative medicine. In addition to these potent physiological functions, these LPLs play pivotal roles in a number of pathophysiological processes. To capitalize on the promise of these molecules in tissue engineering, these lipids have been incorporated into biomaterials for in vivo delivery. Here, we survey the effects of LPA and S1P on both cellular- and tissue-level phenotypes, with an eye toward regulating stem/progenitor cell growth and differentiation. In particular, we examine work that has translational applications for cell-based tissue engineering strategies in promoting cell survival, bone and cartilage engineering, and therapeutic angiogenesis.
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Affiliation(s)
- Bernard Y K Binder
- 1 Department of Biomedical Engineering, University of California , Davis, Davis, California
| | - Priscilla A Williams
- 1 Department of Biomedical Engineering, University of California , Davis, Davis, California
| | - Eduardo A Silva
- 1 Department of Biomedical Engineering, University of California , Davis, Davis, California
| | - J Kent Leach
- 1 Department of Biomedical Engineering, University of California , Davis, Davis, California.,2 Department of Orthopaedic Surgery, School of Medicine, University of California , Davis, Sacramento, California
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The Clinical Status of Stem Cell Therapy for Ischemic Cardiomyopathy. Stem Cells Int 2015; 2015:135023. [PMID: 26101528 PMCID: PMC4460238 DOI: 10.1155/2015/135023] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Accepted: 05/06/2015] [Indexed: 12/14/2022] Open
Abstract
Ischemic cardiomyopathy (ICM) is becoming a leading cause of morbidity and mortality in the whole world. Stem cell-based therapy is emerging as a promising option for treatment of ICM. Several stem cell types including cardiac-derived stem cells (CSCs), bone marrow-derived stem cells, mesenchymal stem cells (MSCs), skeletal myoblasts (SMs), and CD34(+) and CD 133(+) stem cells have been applied in clinical researches. The clinical effect produced by stem cell administration in ICM mainly depends on the transdifferentiation and paracrine effect. One important issue is that low survival and residential rate of transferred stem cells in the infracted myocardium blocks the effective advances in cardiac improvement. Many other factors associated with the efficacy of cell replacement therapy for ICM mainly including the route of delivery, the type and number of stem cell infusion, the timing of injection, patient's physical condition, the particular microenvironment onto which the cells are delivered, and clinical condition remain to be addressed. Here we provide an overview of the pros and cons of these transferred cells and discuss the current state of their therapeutic potential. We believe that stem cell translation will be an ideal option for patients following ischemic heart disease in the future.
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15
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Mastri M, Lin H, Lee T. Enhancing the efficacy of mesenchymal stem cell therapy. World J Stem Cells 2014; 6:82-93. [PMID: 24772236 PMCID: PMC3999784 DOI: 10.4252/wjsc.v6.i2.82] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/20/2013] [Revised: 10/29/2013] [Accepted: 01/14/2014] [Indexed: 02/06/2023] Open
Abstract
Mesenchymal stem cell (MSC) therapy is entering a challenging phase after completion of many preclinical and clinical trials. Among the major hurdles encountered in MSC therapy are inconsistent stem cell potency, poor cell engraftment and survival, and age/disease-related host tissue impairment. The recognition that MSCs primarily mediate therapeutic benefits through paracrine mechanisms independent of cell differentiation provides a promising framework for enhancing stem cell potency and therapeutic benefits. Several MSC priming approaches are highlighted, which will likely allow us to harness the full potential of adult stem cells for their future routine clinical use.
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Binder BYK, Genetos DC, Leach JK. Lysophosphatidic acid protects human mesenchymal stromal cells from differentiation-dependent vulnerability to apoptosis. Tissue Eng Part A 2014; 20:1156-64. [PMID: 24131310 DOI: 10.1089/ten.tea.2013.0487] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
The survival of transplanted cells and their resulting efficacy in cell-based therapies is markedly impaired due to serum deprivation and hypoxia (SD/H) resulting from poor vascularization within tissue defects. Lysophosphatidic acid (LPA) is a platelet-derived growth factor with pleiotropic effects on many cell types. Mesenchymal stromal cells (MSC) exhibit unique secretory and stimulatory characteristics depending on their differentiation state. In light of the potential of MSC in cell-based therapies, we examined the ability of LPA to abrogate SD/H-induced apoptosis in human MSC at increasing stages of osteogenic differentiation in vitro and assessed MSC survival in vivo. Undifferentiated MSC were rescued from SD/H-induced apoptosis by treatment with both 25 and 100 μM LPA. However, MSC conditioned with osteogenic supplements responded to 25 μM LPA, and cells conditioned with dexamethasone-containing osteogenic media required 100 μM LPA. This rescue was mediated through LPA1 in all cases. The addition of 25 μM LPA enhanced vascular endothelial growth factor (VEGF) secretion by MSC in all conditions, but VEGF availability was not responsible for protection against apoptosis. We also showed that codelivery of 25 μM LPA with MSC in alginate hydrogels significantly improved the persistence of undifferentiated MSC in vivo over 4 weeks as measured by bioluminescence imaging. Osteogenic differentiation alone was protective of SD/H-induced apoptosis in vitro, and the synergistic delivery of LPA did not enhance persistence of osteogenically induced MSC in vivo. These data demonstrate that the capacity of LPA to inhibit SD/H-induced apoptosis in MSC is dependent on both the differentiation state and dosage. This information will be valuable for optimizing osteogenic conditioning regimens for MSC before in vivo implementation.
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Affiliation(s)
- Bernard Y K Binder
- 1 Department of Biomedical Engineering, University of California , Davis, Davis, California
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17
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Binder BYK, Sondergaard CS, Nolta JA, Leach JK. Lysophosphatidic acid enhances stromal cell-directed angiogenesis. PLoS One 2013; 8:e82134. [PMID: 24312635 PMCID: PMC3846884 DOI: 10.1371/journal.pone.0082134] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2013] [Accepted: 10/21/2013] [Indexed: 11/19/2022] Open
Abstract
Ischemic diseases such as peripheral vascular disease (PVD) affect more than 15% of the general population and in severe cases result in ulcers, necrosis, and limb loss. While the therapeutic delivery of growth factors to promote angiogenesis has been widely investigated, large-scale implementation is limited by strategies to effectively deliver costly recombinant proteins. Multipotent adipose-derived stromal cells (ASC) and progenitor cells from other tissue compartments secrete bioactive concentrations of angiogenic molecules, making cell-based strategies for in situ delivery of angiogenic cytokines an exciting alternative to the use of recombinant proteins. Here, we show that the phospholipid lysophosphatidic acid (LPA) synergistically improves the proangiogenic effects of ASC in ischemia. We found that LPA upregulates angiogenic growth factor production by ASC under two- and three-dimensional in vitro models of serum deprivation and hypoxia (SD/H), and that these factors significantly enhance endothelial cell migration. The concurrent delivery of LPA and ASC in fibrin gels significantly improves vascularization in a murine critical hindlimb ischemia model compared to LPA or ASC alone, thus exhibiting the translational potential of this method. Furthermore, these results are achieved using an inexpensive lipid molecule, which is orders-of-magnitude less costly than recombinant growth factors that are under investigation for similar use. Our results demonstrate a novel strategy for enhancing cell-based strategies for therapeutic angiogenesis, with significant applications for treating ischemic diseases.
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Affiliation(s)
- Bernard Y. K. Binder
- Department of Biomedical Engineering, University of California Davis, Davis, California, United States of America
| | - Claus S. Sondergaard
- Department of Surgery, Division of Cardiothoracic Surgery, School of Medicine, University of California Davis, Sacramento, California, United States of America
| | - Jan A. Nolta
- Departments of Hematology/Oncology, Cell Biology and Human Anatomy and Stem Cell Program, School of Medicine, University of California Davis, Sacramento, California, United States of America
| | - J. Kent Leach
- Department of Biomedical Engineering, University of California Davis, Davis, California, United States of America
- Department of Orthopaedic Surgery, School of Medicine, University of California Davis, Davis, California, United States of America
- * E-mail:
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Wei H, Wang F, Wang X, Yang J, Li Z, Cong X, Chen X. Lysophosphatidic acid promotes secretion of VEGF by increasing expression of 150-kD Oxygen-regulated protein (ORP150) in mesenchymal stem cells. Biochim Biophys Acta Mol Cell Biol Lipids 2013; 1831:1426-34. [PMID: 23707263 DOI: 10.1016/j.bbalip.2013.05.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2012] [Revised: 04/18/2013] [Accepted: 05/13/2013] [Indexed: 01/16/2023]
Abstract
We previously reported that transplantation of lysophosphatidic acid (LPA) treated mesenchymal stem cells (MSCs) enhances capillary density in the myocardium and improves myocardial function in the ischemic heart. This effect may be mediated through the release of paracrine factors by MSC and potentially involves pro-angiogenic molecules such as vascular endothelial growth factor (VEGF). In this study, we examined the pharmacological and molecular regulation of VEGF secretion induced by LPA in rat MSCs. We showed that LPA stimulated VEGF secretion in MSCs but not in cardiomyocytes or cardiac fibroblasts. LPA-induced VEGF secretion occurred at the post-transcriptional levels and was mediated through the classical ER/Golgi-dependent protein secretory route. LPA also increased ORP150 protein expression. Inhibition of ORP150 upregulation by siRNA knockdown attenuated LPA-induced VEGF secretion. On the other hand, diazoxide, an activator of KATP channel, markedly inhibited LPA-induced ORP150 expression and VEGF secretion. Meanwhile, ATP concentration dependently increased VEGF secretion. In addition, l-Glutamate and NH4Cl significantly reduced VEGF secretion. Furthermore, inhibition of two major subtypes of LPA receptors by Ki16425 and specific siRNA for LPA receptors prevented LPA-induced VEGF secretion and ORP150 expression. Lastly, inhibition of Gi protein that couples with LPA receptors by PTX and siRNA knockdown had no effect on LPA-induced VEGF secretion. Taken together, our findings demonstrate that LPA promotes VEGF secretion at the post-translation level by up-regulating ORP150 expression. Both LPA1 and LPA3 are involved in the LPA-induced VEGF secretion that is independent of Gi protein coupling but associated with the inactivation of KATP channels and inhibition of Na(+)/K(+)-ATPase activity.
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Affiliation(s)
- Hua Wei
- Chinese Academy of Medical Sciences, Beijing, People's Republic of China
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19
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Mohammadzadeh M, Halabian R, Gharehbaghian A, Amirizadeh N, Jahanian-Najafabadi A, Roushandeh AM, Roudkenar MH. Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity. Cell Stress Chaperones 2012; 17:553-565. [PMID: 22362068 PMCID: PMC3535169 DOI: 10.1007/s12192-012-0331-9] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2011] [Revised: 02/05/2012] [Accepted: 02/07/2012] [Indexed: 02/05/2023] Open
Abstract
The most prominent capabilities of mesenchymal stem cells (MCSs) which make them promising for therapeutic applications are their capacity to endure and implant in the target tissue. However, the therapeutic applications of these cells are limited due to their early death within the first few days following transplantation. Therefore, to improve cell therapy efficacy, it is necessary to manipulate MSCs to resist severe stresses imposed by microenvironment. In this study, we manipulated MSCs to express a cytoprotective factor, nuclear factor erythroid-2 related factor 2 (Nrf2) to address this issue. Full-length human Nrf2 cDNA was isolated and TOPO cloned into TOPO cloning vector and then transferred to gateway adapted adenovirus expression vector by LR recombination reaction. Afterwards, the Nrf2 bearing recombinant virus was prepared in appropriate mammalian cell line and used to infect MSCs. The viability and apoptosis of the Nrf2 expressing MSCs were evaluated following hypoxic and oxidative stress conditions. Transient expression of Nrf2 by MSCs protected them against cell death and the apoptosis triggered by hypoxic and oxidative stress conditions. Nrf2 also enhanced the activity of SOD and HO-1. These findings could be used as a strategy for prevention of graft cell death in MSC-based cell therapy. It also indicates that management of cellular stress responses can be used for practical applications.
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Affiliation(s)
- Mohammad Mohammadzadeh
- />Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, P.O. Box 14665-1157, Tehran, Iran
| | - Raheleh Halabian
- />Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, P.O. Box 14665-1157, Tehran, Iran
| | - Ahmad Gharehbaghian
- />Medical Laboratory Sciences Department, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Naser Amirizadeh
- />Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, P.O. Box 14665-1157, Tehran, Iran
| | | | | | - Mehryar Habibi Roudkenar
- />Blood Transfusion Research Center, High Institute for Research and Education in Transfusion Medicine, P.O. Box 14665-1157, Tehran, Iran
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Wang J, Huang W, Wu Y, Hou J, Nie Y, Gu H, Li J, Hu S, Zhang H. MicroRNA-193 pro-proliferation effects for bone mesenchymal stem cells after low-level laser irradiation treatment through inhibitor of growth family, member 5. Stem Cells Dev 2012; 21:2508-19. [PMID: 22384930 DOI: 10.1089/scd.2011.0695] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
The enhanced proliferation of mesenchymal stem cells (MSCs) can be helpful for the clinical translation of cell therapy. Low-level laser irradiation (LLLI) has been demonstrated as regulating MSC proliferation. MicroRNAs (miRNAs) are involved in various pathophysiologic processes in stem cells, but the role of miRNAs in the LLLI-based promotion of MSC proliferation remains unclear. We found that the proliferation level and cell cycle-associated genes in MSCs were increased after LLLI treatment in a time-dependent manner. Microarray assays revealed subsets of miRNAs to be differentially regulated, and these dynamic changes were confirmed by quantitative real-time polymerase chain reaction (qRT-PCR) after LLLI. miR-193 was the most highly up-regulated miRNA, and the change in it was related with the proliferation level. Gain-loss function experiments demonstrated that miR-193 could regulate the proliferation of MSCs, including human's and rat's, but could not affect the apoptosis and differentiation level. Blockade of miR-193 repressed the MSC proliferation induced by LLLI. By qRT-PCR, we found that miR-193, in particular, regulated cyclin-dependent kinase 2 (CDK2) expression. Bioinformatic analyses and luciferase reporter assays revealed that inhibitor of growth family, member 5 (ING5) could be the best target of miR-193 to functionally regulate proliferation and CDK2 activity, and the mRNA and protein level of ING5 was regulated by miR-193. Furthermore, the ING5 inhibited by small interfering RNA (siRNA) could up-regulate the proliferation of MSCs and the expression of CDK2. Taken together, these results strongly suggest that miR-193 plays a critical part in MSC proliferation in response to LLLI stimulation, which is potentially amenable to therapeutic manipulation for clinical application.
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Affiliation(s)
- Jue Wang
- State Key Laboratory of Cardiovascular Medicine, Fuwai Hospital and Cardiovascular Institute, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, China
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21
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Jin P, Wang E, Wang YH, Huang W, Kuang W, Sun C, Hu S, Zhang H. Central zone of myocardial infarction: a neglected target area for heart cell therapy. J Cell Mol Med 2012; 16:637-648. [PMID: 21838808 PMCID: PMC3822938 DOI: 10.1111/j.1582-4934.2011.01408.x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 08/08/2011] [Indexed: 12/17/2022] Open
Abstract
The purpose of this study was to investigate the fate of transplanted cells in the central zone of myocardial infarction (MI), and to clarify the relationship between the injection-site impact and the efficacy of cell therapy. MI was created by coronary ligation in female rats. Three weeks later, 3-million labelled male bone marrow mesenchymal stem cells (BMSCs) were directly injected into the border (BZC group) or central zone (CZC group) of MI area. As a control, culture medium was injected into the same sites. Cell survival was evaluated by quantitative real-time polymerase chain reaction, and apoptosis was assayed with TUNEL and caspase-3 staining. Four weeks after transplantation, heart function and cardiac morphometry were evaluated by echocardiography and Masson's Trichrome staining, respectively. Angiogenesis and myogenesis were detected by immunofluorescence staining. After cell transplantation into the border or central zone, there was no cell migration between the different zones of MI. BMSCs in the CZC group exhibited no difference in apoptotic percentage, in the long-term survival, when compared with those in the BZC group. However, they did effectively promote angiogenesis and cellular myogenic differentiation. Although cell delivery in the central zone of MI had no effect on the recovery of heart function compared with the BZC group, the retained BMSCs could still increase the scar thickness, and subsequently exhibit a trend in the reverse remodelling of ventricular dilation. Hence, we concluded that the central zone of MI should not be ignored during cell-based therapy. Multiple site injection (border+central zone) is strongly recommended during the procedure of cell transplantation.
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Affiliation(s)
- Peifeng Jin
- Department of Surgery and Research Center for Cardiac Regenerative Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
- Department of Thoracic and Cardiovascular Surgery, 1st Affiliated Hospital of Wenzhou Medical CollegeWenzhou, China
| | - Enshi Wang
- Department of Surgery and Research Center for Cardiac Regenerative Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
| | - Ye-huan Wang
- Department of Thoracic and Cardiovascular Surgery, 1st Affiliated Hospital of Wenzhou Medical CollegeWenzhou, China
- Department of Emergency, 1st People Hospital of YueyangYueyang, China
| | - Weicong Huang
- Department of Thoracic and Cardiovascular Surgery, 1st Affiliated Hospital of Wenzhou Medical CollegeWenzhou, China
| | - Wenan Kuang
- Department of Thoracic and Cardiovascular Surgery, 1st Affiliated Hospital of Wenzhou Medical CollegeWenzhou, China
| | - Chengchao Sun
- Department of Thoracic and Cardiovascular Surgery, 1st Affiliated Hospital of Wenzhou Medical CollegeWenzhou, China
| | - Shengshou Hu
- Department of Surgery and Research Center for Cardiac Regenerative Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
| | - Hao Zhang
- Department of Surgery and Research Center for Cardiac Regenerative Medicine, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeBeijing, China
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22
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Targeting lysophosphatidic acid signaling retards culture-associated senescence of human marrow stromal cells. PLoS One 2012; 7:e32185. [PMID: 22359668 PMCID: PMC3281120 DOI: 10.1371/journal.pone.0032185] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2011] [Accepted: 01/23/2012] [Indexed: 01/01/2023] Open
Abstract
Marrow stromal cells (MSCs) isolated from mesenchymal tissues can propagate in vitro to some extent and differentiate into various tissue lineages to be used for cell-based therapies. Cellular senescence, which occurs readily in continual MSC culture, leads to loss of these characteristic properties, representing one of the major limitations to achieving the potential of MSCs. In this study, we investigated the effect of lysophosphatidic acid (LPA), a ubiquitous metabolite in membrane phospholipid synthesis, on the senescence program of human MSCs. We show that MSCs preferentially express the LPA receptor subtype 1, and an abrogation of the receptor engagement with the antagonistic compound Ki16425 attenuates senescence induction in continually propagated human MSCs. This anti-aging effect of Ki16425 results in extended rounds of cellular proliferation, increased clonogenic potential, and retained plasticity for osteogenic and adipogenic differentiation. Expressions of p16(Ink4a), Rb, p53, and p21(Cip1), which have been associated with cellular senescence, were all reduced in human MSCs by the pharmacological inhibition of LPA signaling. Disruption of this signaling pathway was accompanied by morphological changes such as cell thinning and elongation as well as actin filament deformation through decreased phosphorylation of focal adhesion kinase. Prevention of LPA receptor engagement also promoted ubiquitination-mediated c-Myc elimination in MSCs, and consequently the entry into a quiescent state, G(0) phase, of the cell cycle. Collectively, these results highlight the potential of pharmacological intervention against LPA signaling for blunting senescence-associated loss of function characteristic of human MSCs.
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23
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Petite H, Vandamme K, Monfoulet L, Logeart-Avramoglou D. Strategies for improving the efficacy of bioengineered bone constructs: a perspective. Osteoporos Int 2011; 22:2017-21. [PMID: 21523397 DOI: 10.1007/s00198-011-1614-1] [Citation(s) in RCA: 13] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Bioengineered bone scaffolds are intended for use in large bone defects. Successful bone constructs should stimulate and support both the onset and the continuance of bone ingrowth. In an attempt to improve their performance and to compete with the one of autologous bone grafts, a growing symbiosis at the biological and material level is required. Recent advances have been made to further exploit the osteogenic potential of MSCs in scaffold development. Current research encompasses new strategies for reducing cell death after implantation and the manufacturing of tailored, instructive scaffolds.
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Affiliation(s)
- H Petite
- Laboratoire de Bioingénierie et Biomatériaux Ostéo-Articulaires-UMR CNRS 7052, 10 Avenue de Verdun, 75010 Paris, France.
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Wu L, Leijten JCH, Georgi N, Post JN, van Blitterswijk CA, Karperien M. Trophic effects of mesenchymal stem cells increase chondrocyte proliferation and matrix formation. Tissue Eng Part A 2011; 17:1425-36. [PMID: 21247341 DOI: 10.1089/ten.tea.2010.0517] [Citation(s) in RCA: 211] [Impact Index Per Article: 15.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Previous studies showed that coculture of primary chondrocytes (PCs) with various sources of multipotent cells results in a higher relative amount of cartilage matrix formation than cultures containing only chondrocytes. The aim of this study was to investigate the mechanism underlying this observation. We used coculture pellet models of human mesenchymal stem cells (hMSCs) and human PCs or bovine PCs (bPCs) and studied the fate and the contribution to cartilage formation of the individual cell populations during coculture. Enhanced cartilage matrix deposition was confirmed by histology and quantification of total glycosaminoglycan deposition. Species-specific quantitative polymerase chain reaction demonstrated that cartilage matrix gene expression was mainly from bovine origin when bPCs were used. Short tandem repeat analysis and species-specific quantitative polymerase chain reaction analysis of genomic DNA demonstrated the near-complete loss of MSCs in coculture pellets after 4 weeks of culture. In coculture pellets of immortalized MSCs and bPCs, chondrocyte proliferation was increased, which was partly mimicked using conditioned medium, and simultaneously preferential apoptosis of immortalized MSCs was induced. Taken together, our data clearly demonstrate that in pellet cocultures of MSCs and PCs, the former cells disappear over time. Increased cartilage formation in these cocultures is mainly due to a trophic role of the MSCs in stimulating chondrocyte proliferation and matrix deposition by chondrocytes rather than MSCs actively undergoing chondrogenic differentiation.
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Affiliation(s)
- Ling Wu
- Department of Tissue Regeneration, MIRA Institute for Biomedical Technology and Technical Medicine, University of Twente, Enschede, The Netherlands
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25
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Gao F, Hu XY, Xie XJ, Xu QY, Wang YP, Liu XB, Xiang MX, Sun Y, Wang JA. Heat shock protein 90 protects rat mesenchymal stem cells against hypoxia and serum deprivation-induced apoptosis via the PI3K/Akt and ERK1/2 pathways. J Zhejiang Univ Sci B 2010; 11:608-17. [PMID: 20669351 DOI: 10.1631/jzus.b1001007] [Citation(s) in RCA: 42] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Mesenchymal stem cell (MSC) transplantation has shown a therapeutic potential to repair the ischemic and infracted myocardium, but the effects are limited by the apoptosis and loss of donor cells in host cardiac microenvironment. The aim of this study is to explore the cytoprotection of heat shock protein 90 (Hsp90) against hypoxia and serum deprivation-induced apoptosis and the possible mechanisms in rat MSCs. Cell viability was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay. Apoptosis was assessed by Hoechst 33258 nuclear staining and flow cytometric analysis with annexin V/PI staining. The gene expression of Toll-like receptor-4 (TLR-4) and V-erb-b2 erythroblastic leukemia viral oncogene homolog 2 (ErbB2) was detected by real-time polymerase chain reaction (PCR). The protein levels of cleaved caspase-3, Bcl-2, Bcl-xL, Bax, total-ERK, phospho-ERK, total-Akt, phospho-Akt, and Hsp90 were detected by Western blot. The production of nitric oxide was measured by spectrophotometric assay. Hsp90 improves MSC viability and protects MSCs against apoptosis induced by serum deprivation and hypoxia. The protective role of Hsp90 not only elevates Bcl-2/Bax and Bcl-xL/Bax expression and attenuates cleaved caspase-3 expression via down-regulating membrane TLR-4 and ErbB2 receptors and then activating their downstream PI3K/Akt and ERK1/2 pathways, but also enhances the paracrine effect of MSCs. These findings demonstrated a novel and effective treatment strategy against MSC apoptosis in cell transplantation.
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Affiliation(s)
- Feng Gao
- Department of Cardiology, the Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, China
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26
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Zhang H, Yuan X, Jin PF, Hou JF, Wang W, Wei YJ, Hu S. Alteration of parasympathetic/sympathetic ratio in the infarcted myocardium after Schwann cell transplantation modified electrophysiological function of heart: a novel antiarrhythmic therapy. Circulation 2010; 122:S193-200. [PMID: 20837913 DOI: 10.1161/circulationaha.109.922740] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Neural remodeling after myocardial infarction (MI) may cause fatal ventricular arrhythmia. Schwann cells (SCs), which are important for neurogenesis, are dramatically reduced after MI. We investigated the feasibility of modifying nervous system regeneration after MI and the efficacy by which it may prevent ventricular arrhythmia following SC transplantation. METHODS AND RESULTS Immediately after creation of MI, syngenic Lewis rats were randomized into cell transplantation (n=80) and control groups (n=72). SCs were isolated from sciatic nerves, and 5×10(6) cells were intramyocardially injected into the infarct region. Expression levels of myocardial nerve growth factor, vascular endothelial growth factor, growth-associated protein 43, connexin 43, and laminin in the SC group were significantly higher than control at 7 and 14 days after cell transplantation. Immunohistochemical staining illustrated increases in sympathetic and parasympathetic nerves in both groups. However, SC transplantation significantly increased the parasympathetic/sympathetic ratio at 14 days after cell injection. Dynamic electrocardiography and programmed electric stimulation were also performed. The SCs significantly decreased the low-/high-frequency ratio and arrhythmia score of programmed electric stimulation-induced ventricular arrhythmia at 2 weeks after cell injection. However, SCs did not restore heart function. CONCLUSIONS Transplanted SCs in the infarcted myocardium secrete multiple biological molecules, which alter the ratio of parasympathetic/sympathetic nerve density to normalize irritable myocardium. SC transplantation might be a novel cell-based antiarrhythmic therapy following MI.
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Affiliation(s)
- Hao Zhang
- Department of Surgery, Cardiovascular Institute, Fu Wai Heart Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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Jeon ES, Heo SC, Lee IH, Choi YJ, Park JH, Choi KU, Park DY, Suh DS, Yoon MS, Kim JH. Ovarian cancer-derived lysophosphatidic acid stimulates secretion of VEGF and stromal cell-derived factor-1 alpha from human mesenchymal stem cells. Exp Mol Med 2010; 42:280-93. [PMID: 20177148 DOI: 10.3858/emm.2010.42.4.027] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/25/2022] Open
Abstract
Lysophosphatidic acid (LPA) stimulates growth and invasion of ovarian cancer cells and tumor angiogenesis. Cancer-derived LPA induces differentiation of human adipose tissue-derived mesenchymal stem cells (hASCs) to alpha-smooth muscle actin (alpha-SMA)-positive cancer-associated fibroblasts. Presently, we explored whether cancer-derived LPA regulates secretion of pro-angiogenic factors from hASCs. Conditioned medium (CM) from the OVCAR-3 and SKOV3 ovarian cancer cell lines stimulated secretion angiogenic factors such as stromal-derived factor-1 alpha (SDF-1 alpha) and VEGF from hASCs. Pretreatment with the LPA receptor inhibitor Ki16425 or short hairpin RNA lentiviral silencing of the LPA((1)) receptor abrogated the cancer CM-stimulated expression of alpha-SMA, SDF-1, and VEGF from hASCs. LPA induced expression of myocardin and myocardin-related transcription factor-A, transcription factors involved in smooth muscle differentiation, in hASCs. siRNA-mediated depletion of endogenous myocardin and MRTF-A abrogated the expression of alpha-SMA, but not SDF-1 and VEGF. LPA activated RhoA in hASCs and pretreatment with the Rho kinase inhibitor Y27632 completely abrogated the LPA-induced expression of alpha-SMA, SDF-1, and VEGF in hASCs. Moreover, LPA-induced alpha-SMA expression was abrogated by treatment with the ERK inhibitor U0126 or the phosphoinositide-3-kinase inhibitor LY294002, but not the PLC inhibitor U73122. LPA-induced VEGF secretion was inhibited by LY294002, whereas LPA-induced SDF-1 secretion was markedly attenuated by U0126, U73122, and LY294002. These results suggest that cancer-secreted LPA induces differentiation of hASCs to cancer-associated fibroblasts through multiple signaling pathways involving Rho kinase, ERK, PLC, and phosphoinositide-3-kinase.
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Affiliation(s)
- Eun Su Jeon
- Medical Research Center for Ischemic Tissue Regeneration, Medical Research Institute, School of Medicine, Pusan National University, Yangsan 626-870, Korea
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Das R, Jahr H, van Osch GJVM, Farrell E. The role of hypoxia in bone marrow-derived mesenchymal stem cells: considerations for regenerative medicine approaches. TISSUE ENGINEERING PART B-REVIEWS 2010; 16:159-68. [PMID: 19698058 DOI: 10.1089/ten.teb.2009.0296] [Citation(s) in RCA: 224] [Impact Index Per Article: 14.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Bone marrow-derived mesenchymal stem cells (MSCs) have demonstrated potential for regenerative medicine strategies. Knowledge of the way these cells respond to their environment in in vitro culture and after implantation in vivo is crucial for successful therapy. Oxygen tension plays a pivotal role in both situations. In vivo, a hypoxic environment can lead to apoptosis, but hypoxic preconditioning of MSCs and overexpression of prosurvival genes like Akt can reduce hypoxia-induced cell death. In cell culture, hypoxia can increase proliferation rates and enhance differentiation along the different mesenchymal lineages. Hypoxia also modulates the paracrine activity of MSCs, causing upregulation of various secretable factors, among which are important angiogenic factors such as vascular endothelial growth factor and interleukin-6 (IL6). Finally, hypoxia plays an important role in mobilization and homing of MSCs, primarily by its ability to induce stromal cell-derived factor-1 expression along with its receptor CXCR4. This article reviews the current literature on the effects of hypoxia on MSCs and aims to elucidate its potential role in regenerative medicine strategies.
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Affiliation(s)
- Ruud Das
- Department of Orthopaedics, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Zhang H, Chen H, Wang W, Wei Y, Hu S. Cell survival and redistribution after transplantation into damaged myocardium. J Cell Mol Med 2010; 14:1078-82. [PMID: 20646127 PMCID: PMC3822744 DOI: 10.1111/j.1582-4934.2010.01076.x] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2010] [Accepted: 04/21/2010] [Indexed: 02/03/2023] Open
Abstract
A hybrid approach to support cell survival and decrease cell escape Cell transplantation has become an attractive option for cardiac regenerative therapy. However, poor cell survival and extensive redistribution throughout the body can drastically affect the outcome and safety of cell therapy. Although various approaches have been attempted to support the survival and engraftment of implanted cells, we need to apply a new comprehensive strategy by melding the in vitro and in vivo approaches to recondition the cells and infarcted myocardium. Here we summarize our understanding of cell survival and migration after transplantation into the damaged heart.
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Affiliation(s)
- Hao Zhang
- Department of Cardiac Surgery, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical SciencesBeijing, China
- Research Center for Cardiac Regenerative Medicine, the Ministry of HealthBeijing, China
| | - Haibo Chen
- Research Center for Cardiac Regenerative Medicine, the Ministry of HealthBeijing, China
| | - Wei Wang
- Department of Cardiac Surgery, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical SciencesBeijing, China
| | - Yingjie Wei
- Research Center for Cardiac Regenerative Medicine, the Ministry of HealthBeijing, China
| | - Shengshou Hu
- Department of Cardiac Surgery, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical SciencesBeijing, China
- Research Center for Cardiac Regenerative Medicine, the Ministry of HealthBeijing, China
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Giunta S, Castorina A, Adorno A, Mazzone V, Carnazza ML, D'Agata V. PACAP and VIP affect NF1 expression in rat malignant peripheral nerve sheath tumor (MPNST) cells. Neuropeptides 2010; 44:45-51. [PMID: 19919880 DOI: 10.1016/j.npep.2009.10.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2009] [Revised: 09/14/2009] [Accepted: 10/15/2009] [Indexed: 10/20/2022]
Abstract
In our previous study we have identified PACAP, VIP and their receptors in rat malignant peripheral nerve sheath tumor (MPNST) cells, thus showing anti-apoptotic roles. Recently it has been shown that the tumor suppressor neurofibromin, encoded by the Neurofibromatosis type I (NF1) gene, promotes MPNST cells sensitivity to apoptosis after serum withdrawal. In the present study we investigated whether PACAP or VIP negatively regulate NF1 expression under normal or serum-dependent pro-apoptotic culture conditions. Results indicated that serum itself significantly influenced gene and protein levels. In fact, the low NF1 levels of cells cultured in normal serum-containing medium were remarkably increased in cells switched to low- or no-serum after 24h and 48 h. Treatment with 100 nM PACAP or VIP did not affect NF1 expression when using normal amounts of serum, whereas it significantly inhibited transcript and protein levels both in low- or no-serum cultured cells. In particular, PACAP reduced NF1 levels already after 24h in low-serum cultured cells, while VIP showed a similar effect only after serum deprivation. However, both PACAP and VIP downregulated gene and protein levels within 48 h either in low-dose and serum-starved cells. Results were confirmed by fluorescence microscopy, showing that 100 nM PACAP or VIP attenuated neurofibromin cytoplasmic localization only in low- or no-serum cultured cells. The present study provides a comprehensive analysis of both neuropeptides effect on NF1 expression in normal, low- or serum-starved MPNST cells, ameliorating the hypothesis that resistance to apoptosis in serum-deprived cells might be correlated to PACAP-/VIP-induced NF1 inhibition.
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Affiliation(s)
- Salvatore Giunta
- Department of Anatomy, Diagnostic Pathology, Legal Medicine, Hygiene and Public Health, University of Catania, Catania, Italy
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Zhang H, Hou JF, Shen Y, Wang W, Wei YJ, Hu S. Low level laser irradiation precondition to create friendly milieu of infarcted myocardium and enhance early survival of transplanted bone marrow cells. J Cell Mol Med 2009; 14:1975-87. [PMID: 19725921 PMCID: PMC3823279 DOI: 10.1111/j.1582-4934.2009.00886.x] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/09/2023] Open
Abstract
We suggested that low-level laser irradiation (LLLI) precondition prior to cell transplantation might remodel the hostile milieu of infarcted myocardium and subsequently enhance early survival and therapeutic potential of implanted bone marrow mesenchymal stem cells (BMSCs). Therefore, in this study we wanted to address: (1) whether LLLI pre-treatment change the local cardiac micro-environment after myocardial infarction (MI) and (2) whether the LLLI preconditions enhance early cell survival and thus improve therapeutic angiogenesis and heart function. MI was induced by left anterior descending artery ligation in female rats. A 635 nm, 5 mW diode laser was performed with energy density of 0.96 J/cm(2) for 150 sec. for the purpose of myocardial precondition. Three weeks later, qualified rats were randomly received with LLLI precondition (n= 26) or without LLLI precondition (n= 27) for LLLI precondition study. Rats that received thoracotomy without coronary ligation were served as sham group (n= 24). In the cell survival study, rats were randomly divided into 4 groups: serum-free culture media injection (n= 8), LLLI precondition and culture media injection (n= 8), 2 million male BMSCs transplantation without LLLI pre-treatment (n= 26) and 2 million male BMSCs transplantation with LLLI precondition (n= 25) group, respectively. Vascular endothelial growth factor (VEGF), glucose-regulated protein 78 (GRP78), superoxide dismutase (SOD) and malondialdehyde (MDA) in the infarcted myocardium were evaluated by Western blotting, real-time PCR and colorimetry, respectively, at 1 hr, 1 day and 1 week after laser irradiation. Cell survival was assayed with quantitative real-time PCR to identify Y chromosome gene and apoptosis was assayed with transferase-mediated dUTP end labelling staining. Capillary density, myogenic differentiation and left ventricular function were tested by immunohistochemistry and echocardiography, respectively, at 1 week. After LLLI precondition, increased VEGF and GRP78 expression, as well as the enhanced SOD activity and inhibited MDA production, was observed. Compared with BMSC transplantation and culture media injection group, although there was no difference in the improved heart function and myogenic differentiation, LLLI precondition significantly enhanced early cell survival rate by 2-fold, decreased the apoptotic percentage of implanted BMSCs in infarcted myocardium and thus increased the number of newly formed capillaries. Taken together, LLLI precondition could be a novel non-invasive approach for intraoperative cell transplantation to enhance cell early survival and therapeutic potential.
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Affiliation(s)
- Hao Zhang
- Department of Surgery, Cardiovascular Institute and Fu Wai Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
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