\r\n\tIn sum, the book presents a reflective analysis of the pedagogical hubs for a changing world, considering the most fundamental areas of the current contingencies in education.
",isbn:"978-1-83968-793-8",printIsbn:"978-1-83968-792-1",pdfIsbn:"978-1-83968-794-5",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!1,hash:"b01f9136149277b7e4cbc1e52bce78ec",bookSignature:"Dr. María Jose Hernandez-Serrano",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10229.jpg",keywords:"Teacher Digital Competences, Flipped Learning, Online Resources Design, Neuroscientific Literacy (Myths), Emotions and Learning, Multisensory Stimulation, Citizen Skills, Violence Prevention, Moral Development, Universal Design for Learning, Sensitizing on Diversity, Supportive Strategies",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"September 14th 2020",dateEndSecondStepPublish:"October 12th 2020",dateEndThirdStepPublish:"December 11th 2020",dateEndFourthStepPublish:"March 1st 2021",dateEndFifthStepPublish:"April 30th 2021",remainingDaysToSecondStep:"3 months",secondStepPassed:!0,currentStepOfPublishingProcess:4,editedByType:null,kuFlag:!1,biosketch:"Dr. Phil. Maria Jose Hernandez Serrano is a tenured lecturer in the Department of Theory and History of Education at the University of Salamanca, where she currently teaches on Teacher Education. She graduated in Social Education (2000) and Psycho-Pedagogy (2003) at the University of Salamanca. Then, she obtained her European Ph.D. in Education and Training in Virtual Environments by research with the University of Manchester, UK (2009).",coeditorOneBiosketch:null,coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"187893",title:"Dr.",name:"María Jose",middleName:null,surname:"Hernandez-Serrano",slug:"maria-jose-hernandez-serrano",fullName:"María Jose Hernandez-Serrano",profilePictureURL:"https://mts.intechopen.com/storage/users/187893/images/system/187893.jpg",biography:"DPhil Maria Jose Hernandez Serrano is a tenured Lecturer in the Department of Theory and History of Education at the University of Salamanca (Spain), where she currently teaches on Teacher Education. She graduated in Social Education (2000) and Psycho-Pedagogy (2003) at the University of Salamanca. Then, she obtained her European Ph.D. on Education and Training in Virtual Environments by research with the University of Manchester, UK (2009). She obtained a Visiting Scholar Postdoctoral Grant (of the British Academy, UK) at the Oxford Internet Institute of the University of Oxford (2011) and was granted with a postdoctoral research (in 2021) at London Birbeck University.\n \nShe is author of more than 20 research papers, and more than 35 book chapters (H Index 10). She is interested in the study of the educational process and the analysis of cognitive and affective processes in the context of neuroeducation and neurotechnologies, along with the study of social contingencies affecting the educational institutions and requiring new skills for educators.\n\nHer publications are mainly of the educational process mediated by technologies and digital competences. Currently, her new research interests are: the transdisciplinary application of the brain-based research to the educational context and virtual environments, and the neuropedagogical implications of the technologies on the development of the brain in younger students. Also, she is interested in the promotion of creative and critical uses of digital technologies, the emerging uses of social media and transmedia, and the informal learning through technologies.\n\nShe is a member of several research Networks and Scientific Committees in international journals on Educational Technologies and Educommunication, and collaborates as a reviewer in several prestigious journals (see public profile in Publons).\n\nUntil March 2010 she was in charge of the Adult University of Salamanca, by coordinating teaching activities of more than a thousand adult students. She currently is, since 2014, the Secretary of the Department of Theory and History of Education. Since 2015 she collaborates with the Council Educational Program by training teachers and families in the translation of advances from educational neuroscience.",institutionString:"University of Salamanca",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"0",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Salamanca",institutionURL:null,country:{name:"Spain"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"23",title:"Social Sciences",slug:"social-sciences"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"301331",firstName:"Mia",lastName:"Vulovic",middleName:null,title:"Mrs.",imageUrl:"https://mts.intechopen.com/storage/users/301331/images/8498_n.jpg",email:"mia.v@intechopen.com",biography:"As an Author Service Manager, my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. Whether that be identifying an exceptional author and proposing an editorship collaboration, or contacting researchers who would like the opportunity to work with IntechOpen, I establish and help manage author and editor acquisition and contact."}},relatedBooks:[{type:"book",id:"6942",title:"Global Social Work",subtitle:"Cutting Edge Issues and Critical Reflections",isOpenForSubmission:!1,hash:"222c8a66edfc7a4a6537af7565bcb3de",slug:"global-social-work-cutting-edge-issues-and-critical-reflections",bookSignature:"Bala Raju Nikku",coverURL:"https://cdn.intechopen.com/books/images_new/6942.jpg",editedByType:"Edited by",editors:[{id:"263576",title:"Dr.",name:"Bala",surname:"Nikku",slug:"bala-nikku",fullName:"Bala Nikku"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1591",title:"Infrared Spectroscopy",subtitle:"Materials Science, Engineering and Technology",isOpenForSubmission:!1,hash:"99b4b7b71a8caeb693ed762b40b017f4",slug:"infrared-spectroscopy-materials-science-engineering-and-technology",bookSignature:"Theophile Theophanides",coverURL:"https://cdn.intechopen.com/books/images_new/1591.jpg",editedByType:"Edited by",editors:[{id:"37194",title:"Dr.",name:"Theophanides",surname:"Theophile",slug:"theophanides-theophile",fullName:"Theophanides Theophile"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3092",title:"Anopheles mosquitoes",subtitle:"New insights into malaria vectors",isOpenForSubmission:!1,hash:"c9e622485316d5e296288bf24d2b0d64",slug:"anopheles-mosquitoes-new-insights-into-malaria-vectors",bookSignature:"Sylvie Manguin",coverURL:"https://cdn.intechopen.com/books/images_new/3092.jpg",editedByType:"Edited by",editors:[{id:"50017",title:"Prof.",name:"Sylvie",surname:"Manguin",slug:"sylvie-manguin",fullName:"Sylvie Manguin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"3161",title:"Frontiers in Guided Wave Optics and Optoelectronics",subtitle:null,isOpenForSubmission:!1,hash:"deb44e9c99f82bbce1083abea743146c",slug:"frontiers-in-guided-wave-optics-and-optoelectronics",bookSignature:"Bishnu Pal",coverURL:"https://cdn.intechopen.com/books/images_new/3161.jpg",editedByType:"Edited by",editors:[{id:"4782",title:"Prof.",name:"Bishnu",surname:"Pal",slug:"bishnu-pal",fullName:"Bishnu Pal"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"72",title:"Ionic Liquids",subtitle:"Theory, Properties, New Approaches",isOpenForSubmission:!1,hash:"d94ffa3cfa10505e3b1d676d46fcd3f5",slug:"ionic-liquids-theory-properties-new-approaches",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/72.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"1373",title:"Ionic Liquids",subtitle:"Applications and Perspectives",isOpenForSubmission:!1,hash:"5e9ae5ae9167cde4b344e499a792c41c",slug:"ionic-liquids-applications-and-perspectives",bookSignature:"Alexander Kokorin",coverURL:"https://cdn.intechopen.com/books/images_new/1373.jpg",editedByType:"Edited by",editors:[{id:"19816",title:"Prof.",name:"Alexander",surname:"Kokorin",slug:"alexander-kokorin",fullName:"Alexander Kokorin"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"57",title:"Physics and Applications of Graphene",subtitle:"Experiments",isOpenForSubmission:!1,hash:"0e6622a71cf4f02f45bfdd5691e1189a",slug:"physics-and-applications-of-graphene-experiments",bookSignature:"Sergey Mikhailov",coverURL:"https://cdn.intechopen.com/books/images_new/57.jpg",editedByType:"Edited by",editors:[{id:"16042",title:"Dr.",name:"Sergey",surname:"Mikhailov",slug:"sergey-mikhailov",fullName:"Sergey Mikhailov"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"371",title:"Abiotic Stress in Plants",subtitle:"Mechanisms and Adaptations",isOpenForSubmission:!1,hash:"588466f487e307619849d72389178a74",slug:"abiotic-stress-in-plants-mechanisms-and-adaptations",bookSignature:"Arun Shanker and B. Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"4816",title:"Face Recognition",subtitle:null,isOpenForSubmission:!1,hash:"146063b5359146b7718ea86bad47c8eb",slug:"face_recognition",bookSignature:"Kresimir Delac and Mislav Grgic",coverURL:"https://cdn.intechopen.com/books/images_new/4816.jpg",editedByType:"Edited by",editors:[{id:"528",title:"Dr.",name:"Kresimir",surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"18187",title:"Myocardial Tissue Engineering",doi:"10.5772/22870",slug:"myocardial-tissue-engineering",body:'Many lives are lost due to heart diseases including myocardial infarction and cardiomyopathy. Recent reports have demonstrated that regenerative medicine has promising potential for recovering severe heart failure. Regenerative therapies for heart failure include cytokine, gene and cell therapy. Because many types of cardiovascular stem cells have been identified and their clinical potentials have been demonstrated for the past decade, cell injection therapy has most attracted both researchers and clinicians (Wollert 2008). On the other hand, significant cell loss due to washing out and cell death has become problematic in cell injection technique. So, as next generation of regenerative therapy for impaired heart, transplantation of myocardial patches fabricated by tissue engineering technology are emerging and are clinically applied. Furthermore, several challenges for fabricating functional myocardial tissues/organs, which are electrically communicated, pulsate synchronously and evoke contraction power, have also started (Zimmermann, Didie et al. 2006). These ambitious challenges may lead to reconstruction of malformed hearts and become alternative therapy for heart transplantation.
Heart tissues are composed of high-dense cylindrical cardiomyocytes and fibroblasts with abundant vascular network and collagen-based extracellular matrix (ECM). Cardiomyocytes pulsate via sodium and calcium ion transient through cell membrane. They are also electrically coupled by gap junctions composed of connexion 43 and rapid electrical propagation realizes simultaneous beating as a whole. Continuous blood flow supplies oxygen and nutrition, and withdraw the waste for high metabolic demand of heart tissues. These structure and function produce mechanical contractions as a blood pump. Therefore the researchers should take into account high density culture of cardiomyocyte and surrounding cells, sufficient micro blood vessel fabrication, cell/ECM orientation and proper cell-to-cell coupling for engineering heart tissues/organs.
Here, previous and current status of cell injection therapy, myocardial patch transplantation and pulsatile myocardial tissue fabrication is described with some future views.
Cell injection therapy for damaged heart has been researched since the early 1990’s. Many researchers have demonstrated the therapeutic potential of isolated cell transplantation into myocardium using various types of cell sources both in animal models and in some clinical trials (Puceat 2008). The mechanism of myocardial tissue regeneration has not been completely cleared, but most researchers have agreed that transplanted cells secrete several cytokines which promote neovascularization, prohibit fibrosis, decrease cell death and recruit stem cells, leading to heart function improvement. It has been also asserted that some of injected cells differentiate into functional cardiomyocytes and may directly contribute to heart contraction improvement. Although some differences may exist in according to cell types, multifactorial mechanisms seem to relate with myocardial tissue regeneration.
In addition to cell sourcing, different routes are used for cell administration. Systematic intravenous infusion is performed through a central or peripheral vein. This method is simple and less invasive, however widespread distribution cause low ratio of cell engraftment. Most popular approach is intracoronary cell infusion via a balloon-catheter. Injected cells are reached directly in the target myocardial region, however, cells have to transmigrate across endothelium wall. Intracardiac injection is performed via pericardium during open heart surgery and via endocardium by a catheter with a 3-D electromechanical mapping system (NOGA mapping system). These methods realize relatively targeted delivery, but myocardial damage and arrhythmia induction are problematic. Future clarification will be needed to decide which is the best approach for cell injection.
Skeletal myoblasts were the first cell source to enter the clinical application for heart tissue repair. They lie in a quiescent state on the basal membrane of myofibers and have the potential to start to proliferate and differentiate into functional skeletal muscle in response to muscle damage. They can be isolated autologously and be expanded from a single biopsy. In addition, skeketal myoblasts are relatively resistant to ischemia. Menasche and colleagues first applied skeletal myoblast injection via epicardium for patients undergoing coronary artery bypass grafting (CABG) (Menasche, Hagege et al. 2001). The phase I clinical study (MAGIC I) have shown the feasibility of skeletal myoblast implantation, however, increased risk of ventricular arrhythmias after the operation. Then, MAGIC II trial was performed to clarify the safety and efficacy, in which all patients received preventive medication and an implantable cardioverter-defibrillator for rescuing critical ventricular arrhythmias. In result, skeletal myoblast injection failed to significantly improve heart function, leading to sample size reduction (Menasche, Alfieri et al. 2008). On the other hand, the trial indicated the possibility that high dose cell injection might recover left ventricular dilatation. In addition, the other clinical trials of catheter-based myoblast implantation via endocardium have revealed functional efficacy (Opie and Dib 2006). According to these results, not the regenerative potential of myoblasts themselves but the amount of injected cells and delivery system may affect the efficacy. Therefore, it seems that skeletal myoblasts should not be excluded as a cell source for heart tissue repair. More optimization of cell delivery and comparison of cell sources can address these critical issues.
Bone marrow-derived cells are the most used cells in clinical trials for myocardial tissue repair (Wollert 2008). The discovery of circulating progenitor cells originated from human bone marrow has stimulated research and clinical use of bone marrow-derived cells (Asahara, Murohara et al. 1997). Bone marrow cells contain different stem and progenitor cells which will differentiate into various types of cells including endothelial cells, smooth muscle cells and cardiomyocytes. Bone marrow mononuclear cells (BMNCs), which can be isolated simply by gradient sedimentation after bone marrow aspiration without culture expansion, have been clinically injected via coronary artery from the first. BMNCs include heterogeneous cell population of monocytes, hematopoietic stem cells and endothelial progenitor cells (EPCs). Therefore, some groups have used BMNCs selected by surface markers (CD34+, CD133+) and demonstrated more efficacy of their injection. As another cell population, mesenchymal stem cells (MSCs) have been researched and clinically used. Although, MSCs represent between 0.01 and 0.001% of all nucleated cells in bone marrow, they can be readily expanded in culture. MSCs have the potential to differentiate into various types of cells and injected MSCs in heart seem to differentiate into myocardial composing cells. Recent studies have revealed rare happening of cardiomyocyte differentiation, therefore MSCs seem to recover heart function via their cytokine secretion and partial differentiation into vascular cells. As a unique feature, MSCs have the potential to escape from immune detection due to the direct inflammatory inhibition and the lack of cell-surface molecules. This property has realized allogenic mesenchymal stem cell transplantation in clinic and has given high impact on cell therapy research field.
Recent randomized controlled trials of bone marrow-derived cell injection revealed overall feasibility and safety. However the data has revealed only marginal increases of ejection fraction (EF) even in positive studies (0-5%) (Martin-Rendon, Brunskill et al. 2008). For establishing more effective bone marrow-derived cell therapy, optimization of cell source, cell dose, delivery method and deliver timing will be needed.
In addition to bone marrow-derived MSCs, stem cells isolated from the stroma of adipose tissues have represented regenerative potential for heart tissues (Psaltis, Zannettino et al. 2008). Adipose tissue-derived stem cells (ASCs) display features similar to that of bone marrow-derived MSCs and their angiogenic potential have been reported. Some studies have also revealed cardiomyocyte differentiation from ASCs. It has not been clarified which mesenchymal stem cells are superior to other cell types, however, reatively easy isolation of adipose tissue may push the clinical application of ASCs.
Cardiac stem cells (CSCs) are also possible cell source for myocardial tissue regeneration. Two groups first reported CSC existence in 2003 (Beltrami, Barlucchi et al. 2003; Oh, Bradfute et al. 2003). Until then, it was common knowledge that heart was a post mitotic organ, but those reports accelerated the researches for identifying surface marker of CSCs and culturing them. Islet-1, Sca-1 and c-kit have been known as CSC markers. Recently, it has been also confirmed that heart has renewal ability at normal state and the annual rate of turning over is 1% at the age of 25 (Bergmann, Bhardwaj et al. 2009). Although the ability of CSCs may increase after heart injury, newly formed cardyomyocytes are not sufficient for replacing damaged muscle tissues. Therefore isolation and expansion of CSCs have been extensively examined. Some groups have used a different approach to make cardiospheres from biopsied myocardium, which lead to efficient CSC expansion (Lee, White et al. 2011). Clinical trials for injection therapy of autologous CSCs isolated from biopsy sample are now on going.
Although abundant studies demonstrated that MSCs, ASCs and CSCs have the potential of cardiomyocyte differentiation regarding gene and protein expression, there are no studies clearly showing beating cardiomyocytes differentiated from those stem cells. On the other hand, many researchers have confirmed that embryonic stem cells (ESCs) can differentiate into beating cardiomyocytes in vitro and implantation of ESC-derived cardiomyocytes improves damaged heart function. Several signal pathways for cardiac differentiation have been already clarified and various molecules have been reported as its promoters. For example, noggin increased cardiac differentiation efficacy via regulation of Bone morphogenetic protein (BMP) signalling pathway (Yuasa, Itabashi et al. 2005) and insulin-like growth-factor-binding protein 4 (IGFBP4) promotes cardiogenesis by inhibitor of canonical Wnt signalling (Zhu, Shiojima et al. 2008). In addition, fibloblast growth factor (FGF), retinoic acid, ascorbic acid and cyclosporine A have been reported to have the potential to enhance cardiac differentiation from ESCs. The important issue as well as cardiac differentiation is purification of cardiomyocytes from heterogeneous cell mixture, because contamination of immature cells leads to teratoma formation. Although gene-modified ESCs harboring neomycin resistance gene or green fluorescent protein (GFP) gene in the cardiac-specific gene locus are very useful in non-clinical experiments, safe and efficient isolation technologies will be needed for clinical application. Culture media control focusing on the differences of cell metabolism may be useful for safe cell selection. Moreover immune response of the host is another critical issue. Nucler transfer or cell banking is possible approach avoiding immunoreaction.
Electrical communication and simultaneous beating of implanted ESC-derived cardiomyocytes should be also requested for improving damaged heart function without arrhythmia. In vivo electrophisiological analyses and the transplantation technology for synchronization will be essential for clinical application of these cells.
Induced pluripotent stem cells (iPSCs) also hold great promise for myocardial tissue engineering (Vunjak-Novakovic, Tandon et al. 2010). Terminally differentiated cells can be reprogrammed to have the same potential as ESCs by introducing 3 or 4 transcriptional factor genes. Furthemore none-gene transfer technologies have been developed in the world. The superiority of iPSCs to ESCs is autologous cells, which do not cause immune response. Cardiac differentiation of human iPSCs has been reported in the same manner with ESCs.
Several critical issues must be clarified for clinical use, but ESCs/iPSCs-derived cardiomyocytes should contribute to myocardial tissue engineering in the view point of their pulsatile function and scaling-up.
Cell injection therapies for heart failure are now world-widely performed. While moderate success of direct cell injection has been observed, the efficacies seem not to reach the level that general clinicians think cell therapy a reliable treatment for heart failure. More optimization of cell source, cell preparation process, injection route, injection timing and patient population may increase the effectiveness; however one of the essential issues is cell delivery methodology. Cell injection therapy has significant difficulties about cell retention in the target tissue. The shape, size, and position of the grafted cells are often uncontrollable and large amount of the cells are washed-out. Moreover, once retaining cells die due to necrosis and apoptosis. Time course quantification with TUNEL assay demonstrated that a large number of the grafted cells die within a few days after injection in rat models (Zhang, Methot et al. 2001). In the clinical trial using bone marrow-derived cells, it has been also demonstrated that only 1-3% of the cells infused via coronary arteries could be detected by 3D positron emission tomography (PET) imaging of the patient heart. In this study, a large percentage of cells were found in the liver and spleen immediately after the procedures (Hofmann, Wollert et al. 2005). To clear the problem of cell loss, hydrogel-cell mixture injection has been pursued. Fibrin, collagen and alginate hydrogels are now used. Hydrogels with cells are injected as a liquid phase through syringe or catheter, then, they are polymerized and fixed in the target tissues (Kofidis, de Bruin et al. 2004). In hydrogel-cell mixture injection therapy, local tissue damage due to space occupation of hydrogel itself and inflammatory reaction due to hydrogel biodegradation are problematic.
Therefore, more advanced cell delivery systems have been requested to spread the regenerative therapy as one of the reliable treatments for heart failure.
Recent advance of tissue engineering technologies have realized the transplantation of tissue-engineered construct “myocardial patch” covering over damaged heart surface instead of simple cell injection into myocardium. Grafted cells within myocardial patches can survive more and secrete more cytokines, resulting in more heart function improvement. Furthermore pulsatile myocardial tissues have been successfully engineered by using cardiomyocytes as a seeding cell source. These tissues may directly help heart contraction and total heart wall replacement may be possible in future. There are several contexts of tissue engineering.
Most popular technology of tissue engineering is to seed cells into 3-D pre-fabricated biodegradable scaffolds which are made from synthetic polymer and biological material. Hydrogel formation after mixing cells and scaffold solution is another approach. Decellularized tissues have been also used as scaffolds. These scaffolds play as alternatives for extra cellular matrix (ECM), therefore, their cell-adhesiveness and porosity affect survived cell amount and engineered tissue quality. Scaffold modification can control its biodegradation and tissue formation. Growth factor linkage leads to accelerating tissue formation. Now these scaffold-based tissue engineering has been widely applied to cardiovascular tissue regeneration as well as other tissue repair (Vunjak-Novakovic, Tandon et al. 2010).
In contrast to scaffold-based tissue engineering, our group have developed unique technique involving cell sheet stacking to fabricate 3-D tissues (Shimizu, Yamato et al. 2003). Cell sheets are 2-D connecting pure cells without any scaffolds, therefore cell-dense 3-D tissues can be fabricated by stacking cell sheets. Cell sheets are harvested from intelligent culture surface “temperature-responsive culture surface”, which are covalently grafted with temperature-responsive polymer, poly (N-isopropylacrylamide) (PIPAAm) (Okano, Yamada et al. 1993). The surfaces are slightly hydrophobic and cell-adhesive at 37˚C, on the other hand, the surface changes to hydrophilic and not cell adhesive below 32˚C. Confluently cultured cells on the surface can detach as a contiguous cell sheet simply by reducing temperature. Furthermore, biological molecules underneath cell sheets are also preserved and play a critical role as an adhesive agent during cell sheet stacking. Cell sheet-based tissue engineering has been applied for a wide range of regenerative medicine including corneal epithelial replacement, heart tissue repair, pneumothorax repair, liver tissue repair and so on.
According to the spread of the concept fabricating 3-D tissues from 2-D confluent cells, several other technologies using this concept have emerged. Cell sheet fabrication techniques using fibrin coated dishes or nanofibrous polycaprolactone meshes have been reported (Shin, Ishii et al. 2004; Itabashi, Miyoshi et al. 2005). Cell sheet-like constructs have been also engineered using magnetite nanoparticles (Ito, Hibino et al. 2005). Magnetically labelled cells are attached on culture materials by magnetic force and confluent cells are harvested as a cell sheet by magnetic force release. Thus, cell sheet-based tissue engineering has now spread in the world as scaffold-free tissue engineering.
Both scaffold-based and cell sheet-based tissue engineering have been used for myocardial patch fabrication. Not only cardiomyocytes but also other types of cells have been used for creating myocardial patches and some myocardial patches using non-cardiomyocytes have been already clinically transplanted over damaged hearts. (Fig. 1.)
In myocardial patch fabrication, synthetic polymer, biological material and decellularized tissue have been used as prefabricated scaffolds. Li and colleagues, who were one of the pioneer groups of myocardial tissue engineering, first demonstrated that gelatine sponges seeded with cardiac cells have therapeutic potentials for cryoinjured rat hearts (Li, Jia et al. 1999). Leor and colleagues reported that bioengineered heart grafts using porous alginate scaffolds attenuated left ventricular dilatation and heart function deterioration in infarction model (Leor, Aboulafia-Etzion et al. 2000). Eschenhagen and Zimmermann’s group have developed innovative myocardial tissue engineering approach (Zimmermann, Schneiderbanger et al. 2002). They have fabricated 3-D tissues by gelling mixture of cardiac cells and collagen solution. The constructs induced systolic wall thickening of the left ventricle infracted area and improved fractional shortening of damaged hearts in rat myocardial infarction model (Zimmermann, Melnychenko et al. 2006). Small intestinal submucosa (SIS) has also been used as a scaffold for myocardial patch. MSC-seeded SIS improved heart contraction in rabbit infarction model (Tan, Zhi et al. 2009). There have been various types of myocardial patches using different scaffolds and different cell sources. Although implantable human myocardial patches using beating cardiomyocytes have not been established now, clinical trials of collagen-based myocardial patch with bone marrow cells (MAGNUM trial) (Chachques, Trainini et al. 2007) and vicryl mesh-based myocardial patches with fibroblasts (Anginera) ((Mirsadraee, Wilcox et al. 2006)) have revealed feasibility and safety of myocardial patch transplantation.
Tissue engineering (TE) strategies for myocardial patch fabrication
Many types of cell sheets have been reported to improve impaired heart function (Shimizu, Sekine et al. 2009). Cell sheets are transplanted onto heart surface directly via open heart surgery and cells can be more effectively delivered as thin, but large-area cell-dense grafts than isolated cell injection. Scaffold-based myocardial patches are usually transplanted on myocardium with suture, on the other hand, cell sheets are transplanted with no suture because biological adhesive proteins underneath cell sheets promote the attachment. When neonatal rat cardiac cell sheets were transplanted onto infracted rat hearts, grafted cardiomyocytes communicated with host myocardium via gap junctions and blood vessels formed within the graft, resulting in significant improvement of heart function (Miyagawa, Sawa et al. 2005; Sekine, Shimizu et al. 2006).
Sawa and colleagues have started to use skeletal myoblasts for cell sheet fabrication, because myoblasts can be isolated autologously and are relatively resistant to ischemic condition. The recovery of heart function by skeletal myoblast transplantation has been confirmed in rat ischemic model, in dilated cardiomyopathy hamster model, in pacing-induced canine heart failure model and in pig infarction model (Memon, Sawa et al. 2005; Hata, Matsumiya et al. 2006; Kondoh, Sawa et al. 2006; Miyagawa, Saito et al. 2010). Regarding stacking cell sheet number, 3-5 layers are optimal and more layering cause primary necrosis of the constructs (Sekiya, Matsumiya et al. 2009). They have demonstrated more hematopoietic stem cells and less fibrosis in cell sheet transplantation than in isolated cell injection in accordance with more expression of stromal-derived factor 1 (SDF-1), hepatocyte growth factor (HGF), and vascular endothelial growth factor (VEGF). Based on these results, clinical trial of autologous myoblast sheet transplantation for severe heart failure has started and the detailed results will appear soon.
In the same manner with cell injection therapy, MSCs are used as a candidate cell source for human implantable cell sheet. Adipose tissue-derived MSCs and menstrual blood-derived MSCs have improved damaged heart function in rat infarction model (Miyahara, Nagaya et al. 2006; Hida, Nishiyama et al. 2008). MSCs can gradually grow to form a thick stratum containing newly formed blood vessels and some cells seem to differentiate into cardiomyocytes at least by histological analyses. Further studies will be needed to confirm the differentiation into functional beating cardiomyocytes and possibilities to differentiate into unexpected cell types.
As emerging cell source, cell sheets of stem cell antigen 1-positive (Sca-1-positive) CSCs ameliorates cardiac dysfunction in mouse infarction model through cardiomyocyte differentiation and paracrine mechanisms mediated via soluble vascular cell adhesion molecule 1 (VCAM-1)/very late antigen-4 (VLA-4) signaling pathway (Matsuura, Honda et al. 2009). In addition, cardiac cell sheets originated from ESCs/iPSCs have been successfully fabricated and their transplantation into animal models is now ongoing.
For enhancing the efficacy of cell sheet transplantation, gene-modified cell sheets have been examined. Bcl-2 expressed myoblast sheets prolonged survival, increased production of proangiogenic paracrine mediators, and enhanced the therapeutic efficacy (Kitabayashi, Siltanen et al. 2010). HGF overexpression in myoblast sheets enhances their angiogenic potential in rat chronic heart failure model (Siltanen, Kitabayashi et al. 2011). As another concept, cell sheets co-cultured with endothelial cell sources have been transplanted in rat infarction models. Transplantation of EPC co-cultured fibroblast sheet improved heart function more than only fibroblast sheet implantation or EPC injection (Kobayashi, Shimizu et al. 2008). Furthermore, endothelial cell co-culture within cardiomyocyte sheets induced more neovascularization and more improvement of cardiac function than only cardiomyocyte sheets (Sekine, Shimizu et al. 2008). These studies indicate advanced strategies of cell sheet transplantation.
As mentioned previously, it is considered that the main mechanism of heart function improvement is neovascularization, fibrosis inhibition, apoptosis inhibition and stem cell recruitment due to various cytokines secreted from grafted cells. In comparison with cell injection approach, increase of cell survival within myocardial patches leads to more cytokine secretion, then, resulting in more function improvement. In addition to cytokine secretion, myocardial patches may have girdling effect and prohibit heart dilatation. Therefore, myocardial patch transplantation is quite different cell delivery method from cell injection and has more potential to rescue diseased hearts. In the case of myocardial patches using beating cardiomyocytes, direct enhancement of contraction power is additionally expected, however, electrical synchronization between host hearts and transplanted patches is a critical issue to be clarified.
Beyond myocardial patch fabrication, several research groups have challenged to fabricate pulsatile myocardial tissues by their original tissue engineering strategies. Bioengineered contractile myocardial tissues may realize new therapeutics for severe heart diseases and be useful as alternatives for animal models.
The first approach for engineering functional myocardial tissue is seeding cardiomyocytes into synthetic or biological 3-D scaffolds. Vunjak-Novakovic and colleagues first reported that seeding primary cultured cardiomyocytes onto disc-shaped polyglycolic acid (PGA) scaffolds in rotating bioreactor system resulted in spontaneously pulsatile myocardial tissues (Papadaki, Bursac et al. 2001). Optimization of cell population, serum concentration and scaffold coating improved electrical conduction velocity of engineered constructs. Radisc and colleagues seeded rat cardiomyocytes in Matrigel onto collagen sponges and stimulated the constructs electrically. The stimulation improved the conductive and contractile properties in accordance with increased expression of myosin heavy chain and connexion 43. Furthermore, cardiomyocytes in the electrically stimulated constructs were more aligned and elongated as same as those in native heart tissue (Radisic, Park et al. 2007).
Following these studies, many research groups have started to engineer myocardial tissue in vitro by using various types of scaffolds. Scaffold porosity is one of the critical factors for pre-fabricated scaffold-based tissue engineering. High porosity increases seeded cell number and facilitates mass transport. Surface modyfication is also important for cell attachment and survival. Laminin coating improved cardiomyocyte adhesiveness. In addition, scaffold elasticity and degradability affect contraction property of engineered myocardium. Further studies are ongoing to development appropriate scaffold materials for myocardial tissue engineering.
The second approach is to form 3-D tissues by gelling of cardiac cell and matrix solution mixture. Eschenhagen and Zimmermann have continuously developed this strategy using collagen gel and successfully engineered macroscopically beating cardiac tissues (Zimmermann and Cesnjevar 2009). First, neonatal rat cardiomyocytes were suspended in collagen I solution and the mixture was poured into the mold. After gelling, the constructs were unidirectionally stretched with the mechanical devise. They have also realized contraction force measurement. Cyclic stretch introduced cell alignment along the stretching direction and increased mitochondrial density, leading to native heart-like tissue. The contraction force of engineered myocardium was comparative with native heart tissue and responded to pharmacological agents properly. Ring-shaped myocardial tissues were also fabricated and combined 5 constructs were transplanted onto infarcted rat hearts. Interestingly, the constructs synchronized to each other and improved damaged heart function. They have also confirmed that co-culture constructs including cardiomyocytes, fibroblasts and endothelial cells were superior to cardiomyocyte rich constructs in morphology and function. Recently, they have also started to utilize human cardiomyocytes differentiated from ESC/iPSC as cell source and challenged to create human myocardial tissues (Zimmermann 2011). In contrast to pre-fabricated scaffold usage, relatively homogeneous myocardial tissues are engineered by hydrogel-based approach. Therefore collagen gel-based myocardial tissue engineering has now become popular in the world.
The third approach is to engineer 3-D pulsatile myocardial tissues by stacking cardiac cell sheets. As mentioned previously, 2-D cell sheets can be harvested from temperature-responsive culture dishes only by lowering temperature and do not include any materials. 3-D tissues are constructed by layering cell sheets. Because 2-D confluent cells are directly stacked without any scaffolds, resulting constructs are cell-dense 3-D tissues. It is well-known that 2-D confluent cardiomyocytes connect to each other electrically via gap junctions resulting in synchronized beating. Cardiac cell sheets harvested from temperature-responsive culture dishes maintain this synchronized pulsation (Shimizu, Yamato et al. 2002). For creating 3-D functional heart tissues by layering cardiac cell sheets, morphological and electrical communications between cell sheets are critical. Multiple-electrode extracellular recording system revealed that double-layer rat cardiac cell sheets coupled electrically about one hour after layering and histological analysis showed the existence of connexin 43 between two cardiac cell sheets. Adhesive proteins deposited on cell sheet surface are considered to promote these rapid electrical communications (Haraguchi, Shimizu et al. 2006). Stacked cardiac cell sheets beat synchronously in macroscopic view and the constructs transplanted into rat subcutaneous tissues also pulsated continuously at least up to one year and eight months after implantation. Morphological analyses showed elongated cardiomyocytes, well-differentiated sarcomeres, gap junctions and multiple blood vessels, which were characteristic structure of native heart tissue (Shimizu, Yamato et al. 2002). Long-term observation revealed that their size, conduction velocity, and contractile force increased in proportion to the host growth (Shimizu, Sekine et al. 2006). Recently, fabrication of cardiac cell sheets using ESC-originated cardiomyocytes have just started and human cardiac cell sheets will appear in near future.
One of the major obstacles in myocardial tissue engineering is scaling-up of the constructs. Insufficient supply of oxygen and nutrient, and waste accumulation limit their thickness. Actually, cells are sparse in the central area, on the other hand, cells are dense in the outer surface (100-200μm) area in scaffold-based myocardial tissue engineering. In the case of cell sheet-based myocardial tissue engineering, thickness limit is approximately 80μm (3 layers) (Shimizu, Sekine et al. 2006). Several approaches have been examined in the point of view overcoming diffusion limit. Perfusion of culture media through the constructs using porous scaffolds is one possible approach. Media penetration increased cell migration depth and improved cell metabolism. However shear stress due to media flow may prohibit tight cell attachment on the scaffold material. Media perfusion with oxygen carrier, perfluorocarbon (PFC) has been also examined for improving oxygen transport. PFC usage increased cell proliferation and improved pulsatile function. Media penetration is useful to some extent, however, it becomes more difficult as cell density increases.
To overcome this problem, it has been requested to develop new technologies for introducing vasculature or vascular-like structure into engineered tissues. Several researchers have tried to generate microchannel network within porous 3-D scaffolds by microfabrication techniques including CO2 laser ablation. The technology has not reached to mimicking native micro capillary network. On the other hand, recent studies have revealed that co-cultured endothelial cells within cardiac constructs can spontaneously form vascular-like network in vitro and tubular formation has been found in some parts. It has been also confirmed that this pre-vascular structure connected to host blood vessels immediately after transplantation and the newly developed vessels within the constructs were blood-supplied within a few days (Sekiya, Shimizu et al. 2006). We have already demonstrated that the tissue thickness of cardiac cell sheets co-cultured with endothelial cells were just twice as the thickness of cardiac cell sheets without endothelial cells (Sekine, Shimizu et al. 2008). Although endothelial cell co-culture is helpful for accelerating blood vessel formation, more scaling-up is still limited due to primary ischemia until sufficient vascularization.
One possible idea for scaling-up is utilizing in vivo vascularization power. Our group has reported that triple-layer cardiac cell sheets were repeatedly implanted after waiting enough vascular formation within previously implanted tissues. In result, synchronously beating thick myocardial tissues with sufficient micro capillaries were successfully fabricated and 10-times transplantation of triple-layer constructs (totally 30 sheets) formed 1-mm thick, pulsatile myocardial tissues. Furthermore, when triple-layer grafts were transplanted repeatedly over a surgically connectable artery and vein in leg, the multilayer constructs were blood-supplied from the thick artery and vein. The constructs were successfully resected with the connectable blood vessels and were ectopically transplanted in neck with direct vessel anastomoses (Shimizu, Sekine et al. 2006). Recently several groups have also utilized in vivo power for myocardial tissue engineering. Cardiomyocytes, ECM alternatives and native blood vessels were packed in the special chamber and incubated in vivo. Vascularized heart-like tissues were created in the body (Morritt, Bortolotto et al. 2007; Birla, Dhawan et al. 2009).
Furthemore, next challenge is now in vitro fabrication of vascularized myocardial tissues. Kofidis and colleagues have constructed fibrin gel-based myocardial tissues containing rat aortas (1-2mm), through which culture media was perfused (Kofidis, Lenz et al. 2003). Cell survival and metabolism were improved, however formation of functional blood vessels connecting with central aortas were not clear. We are now trying to promote endothelial cell tubular formation within in vitro engineered cardiac tissues and to perfuse culture media through the newly formed vessels using perfusion bioreactors. Further studies will be needed to break through the obstacles for in vitro scaling up.
For future organ engineering, some groups have challenged to engineer myocardial constructs with pumping function. Ott and colleagues have used decellularized organ as a scaffold. They decellularized rat whole hearts and re-seeded cardiac cells into decellularized hearts. Heart contraction was recovered and pump function was generated (Ott, Matthiesen et al. 2008). Zimmermann’s group developed pouch-like myocardial tissue by their technology as previously described and covered heart with pouch-like constructs (Yildirim, Naito et al. 2007).
Regarding cell sheet technology, myocardial tubes have been fabricated by wrapping rat cardiac cell sheets around fibrin tubes and rat resected aortas. The engineered myocardial tubes revealed spontaneous, synchronized pulsation and small but significant inner pressure changes (about 0.1 mmHg) in vitro (Kubo, Shimizu et al. 2007). On the other hand, resected rat aortas wrapped with cardiac cell sheets were micro surgically transplanted in place of the abdominal aorta. After 1 month, in vivo myocardial tubes demonstrated spontaneous beating and evoked independent blood pressures (about 6 mm Hg). The value of in vivo myocardial tubes was much bigger than in vitro myocardial tubes (Sekine, Shimizu et al. 2006). Comparing in vitro and in vivo, it was considered that pulsation due to host blood flow has induced cardiomyocyte hypertrophy, leading to improvement of pumping function. Therefore pulsatile perfusion bioreactors may improve pumping function of in vitro engineered myocardial tubes.
Thus, small size myocardial constructs evoking pumping function have been realized. Expansion and selection of cardiomyocytes, and sufficient blood vessel formation for scaling-up are now critical issues for organ engineering.
As the first generation of cardiac regenerative therapy, many clinical trials of cell injection therapy have been already performed. The controversial arguments about its effectiveness will be settled in next several years. Tissue engineered myocardial patches have now emerged as the second generation and previous studies indicate promising potential for rescuing damaged heart. As the third generation, tissue-engineered pulsatile myocardial tissues should support heart contraction physically. Furthermore, future development of cell sourcing and scaling-up technologies may realize “bioengineered hearts”.
This work is granted by the Japan Society for the Promotion of Science (JSPS) through the “Funding Program for World-Leading Innovative R&D on Science and Technology (FIRST Program),” initiated by the Council for Science and Technology Policy (CSTP).
Changing food habits, sedentary lifestyle and obesity has made type 2 diabetes (T2D) a global epidemic. T2D has various characteristic features such as insulin resistance caused when peripheral tissues such as liver, muscle and adipocytes have a decreased response to insulin. The progression from normal glucose tolerance to type 2 diabetes involves several transitional stages of impaired fasting glucose and impaired glucose tolerance which is known as prediabetes. The mechanism leading to the development of these glucose metabolic alterations is multifactorial. The most prevalent factor of T2D is insulin resistance that occurs when peripheral tissues such as liver, muscle and adipocytes, the main target organs of Insulin hormone, loses the ability to respond to insulin [1]. Generally in the obese patients without T2D and initially in people who develop insulin resistance, pancreatic β-cells are able to compensate for insulin resistance by increasing insulin secretion by increasing β-cell mass via increased proliferation and hypertrophy [2, 3]. Increasing of β-cells in a compensatory mechanism to avoid the complications caused due to insulin resistance and henceforth prevents diabetes [4]. This unique mechanism of β-cell mass expansion has been observed in normal individuals during physiological growth [5] as well as in insulin resistant patients, especially pregnant women [6] and obese people [7]. In patients having T2D the initial stage of β-cell compensation is followed by dysfunction or failure of β-cells due to less proliferation and increased apoptosis [1, 8].
\nPancreatic β-cell dysfunction plays a critical role in progression of T2D. Insulin is produced as preproinsulin and then processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretory granules. Synthesis of insulin is regulated at both transcription and translational level. Several transcription factors in the cis-acting sequences within the 5′ region and trans-activators regulate insulin gene transcription. These transcription factors are paired homeobox gene 6 (PAX6), pancreatic and duodenal homeobox-1 (Pdx-1), MafA and B-2/Neurogenic differentiation 1 (NeuroD1). Insulin secretion from β-cells contains a series of events and is controlled by variety of factors and signaling pathways that ultimately leads to the fusion of secretory granules with the plasma membrane. The various stimulants that regulate insulin secretion are glucose, free fatty acids, amino acids, also various hormones like melatonin, estrogen, leptin, growth hormone and glucagon like peptide-1 [9].
\nThe monomeric structure of insulin is made up of “A” chain with 21 amino acids and “B” chain with 30 amino acids, which are bound by disulfide bonds. Actually three disulfide bonds are present in the structure of insulin monomer, two in between the A and B chains (A7–B7, A20–B19) and one within the A chain (A7–A11) [10]. The secondary structure of the A chain is made up of two anti-parallel α-helices in between A2–A8 and A13–A19 residues. Also the helices are connected by residues at A9–A12. As a result of this particular arrangement the two ends remains in close proximity to each other and side by side [11].
\nThe B chain is made up of α-helices and β-pleated sheets [11] and in the T state it exists in two different conformations in crystallized form [12]. The α-helix exists between B9 and B19, a β-turn between B20 and B23 and the chain folds in a “V” due to Gly20 and Gly23. An extended β-strand structure in between residues B24 and B30 which allows the chain to be in close proximity to form a β-sheet with PheB24 and TyrB26 which are in close contact with B11 and B15 leucine residues of α-helix. There is a continuous α-helix from B1 to B19 in the R state. The stability of the native insulin structure is due to the disulfide bonds in between Cys residues A7–B7 and A20–B19. The affinity of insulin towards the insulin receptor is determined by the side chain interactions in between A chain and B chain. These disulfide bonds between the A and B chain provide the tertiary structure of insulin monomer which is very highly organized. The various amino acid interactions in the side chain also contribute to the stable tertiary structure of the insulin monomer molecule. These interactions are also responsible for the interaction or affinity of insulin towards its receptor [11].
\nThe hydrophobic inner core of the insulin monomer is composed of the following amino acids residues: A6–A11 and Leu A11, B1 and B15, Ile A2, Phe B24, Val A3, Ile A13, Val B18 and Val B12. The amino acid residues from B20 to B23 are necessary for stabilizing the β-turn thereby leading to the folding of the β-sheet in between B23 and B30 towards the α-helix and hydrophobic inner core. In the dimeric form of insulin these non-polar amino acids remain in the inner side. The insulin subunits generally remain as dimers [12]. The dimeric form of insulin is stabilized by the antiparallel β-sheets at the carboxy terminals of the B chains which remain expose on the surface of the dimeric structure. The hydrophobic core of the insulin dimer is composed of non-polar residues [11].
\nThere are three dimers made up of six molecules of insulin peptide to make a hexamer. Some differences in the side chain like in the 25th residue (Phe) in the B chain, which is arranged to be inside the hydrophobic core of the peptide chain on one side of the dimer, deforms the perfect two-fold symmetry [11]. Also there are two zinc atoms with the imidazole groups in three histidine residues in the B chain along with two water molecules in the insulin hexamer [12].
\nThe knowledge about the structure of insulin is necessary to understand its interaction with insulin receptor. The amino acids in the specific regions of the insulin molecule that facilitate its binding with the receptor are located at the amino terminal of the A chain: GlyA1, IleA2, ValA3, GluA4: carboxy terminal of the A chain: TyrA19, CysA20, AsnA21; and carboxy terminal of the B chain: GlyB23, PheB24, PheB25, TyrB26. These residues have are denoted as the “cooperative site” of the insulin due to their negative cooperativity [13, 14].
Out of the two chains in the structure of insulin, the A chain has more significant role for binding to the receptor. Acetylation of the amino terminal reduces binding to receptor by 30% which makes a free amino terminus necessary for binding to receptor [15].
Gly1 deletion reduces binding to receptor by 15% which may be due to some salt bridge formation between Gly1 and B chain carboxy terminus [16].
Also TyrA19, CysA20 and AsnA21 in the carboxy terminus of the A chain are also necessary for insulin receptor activity [16].
The carboxy terminal of the B chain has also a significant role in the receptor binding activity, specially the first four residues, whose deletion reduces receptor binding activity by 30% [17, 18].
Fifteen percent of the receptor binding activity is detained when HisB5 is deleted and 1% of binding activity is reduced when LeuB6 is deleted [19].
For the maintenance of disulfide bonds between A and B chain, CysB7 is critical [20].
HisB10 is necessary for activity because when substituted with AspB10, proinsulin is not converted to insulin [21].
However, synthetic insulin containing AspB10 has 500% greater binding affinity than normal insulin [22].
PheB24 forms hydrogen bonds important for dimer formation and PheB25 is important for conformation of the native insulin structure [16].
GlyB23, PheB24, PheB25 and TyrB26 in the B chain carboxy terminus are evolutionarily conserved residues needed for receptor binding [16] (Figure 1).
Structure of insulin [10, 11, 12, 20].
The various stimulants in blood that lead to insulin secretion are glucose, monosaccharide, amino acid and fatty acid.
\nGlucose acts as the main stimulus for insulin secretion in rodents as well as human beings because it is one of the major constituents of their diet and enters the circulation immediately after digestion of food. Glucose transporter 2, i.e., GLUT2 is the main glucose sensor found in the plasma membrane of β-cells. Translocation of GLUT2 to plasma membrane is dependent on insulin and it bears low substrate affinity, hence leading to high uptake of glucose. Upon entry into β-cell glucose is phosphorylated to glucose-6-phosphate by glucokinase, a type of hexokinase. Glucokinase is the rate-limiting step in the glucose metabolism in β-cells [23]. Since pyruvate dehydrogenase is not found in β-cells, pyruvate is metabolized to produce metabolic coupling factors via two pathways: (a) pyruvate is metabolized to acetyl-coA and thereby it enters glucose oxidation: the main signaling pathway couple to pyruvate oxidation through the tricarboxylic acid cycle (TCA) by mitochondria “ATP-sensitive potassium (KATP) channel-dependent insulin release.” The other pathway is anaplerosis where pyruvate, like other TCA cycle intermediates is replenished. However, some of the products of these processes can act as signals stimulating release of insulin, like malonyl-CoA, NADPH, and glutamate. These products are known to amplify KATP channel-dependent insulin secretion [24, 25].
\nFormation of glycerol-3-phosphate (Gly3P) is the third glucose signal. Glucokinase phosphorylates glucose into glucose-6-phosphate (G6P), G6P then enters glycolysis to produce pyruvate. Gly3P can also be produced by G6P via dihydroxyacetone phosphate (DHAP) pathway. These compounds stimulate insulin secretion. Gly3P also promotes β-cell glycolysis via the mitochondrial Gly3P NADH shuttle process, which activates mitochondrial energy metabolism and augments insulin secretion [26, 27]. Dysfunction of β-cells after prolonged exposure to elevated levels of glucose has been linked to changes in glucose detection and metabolism, apoptosis, and calcium handling. Now it has already been reported that glucotoxicity impedes final steps in insulin secretion, i.e., exocytosis [28].
\nFree fatty acids (FFAs) exert both positive and negative effects on β-cell survival and insulin secretory function, depending on concentration, duration, and glucose abundance. Insulin secretion from β-cell is also stimulated by free fatty acids (FFAs). The FFAs can also upregulate glucose stimulated insulin secretion (GSIS) from β-cells. In total absence of FFAs the β-cells lose their insulin secreting capability which can again be restored when exogenous fatty acids are added [29, 30, 31]. The FFAs act upon β-cells through free fatty acid receptor (FFAR)-1, hence controlling β-cell function [32, 33]. The intracellular metabolism of FFA leads to the production of lipid signal molecules like long-chain acyl-CoA and DAG [34]. DAG in turn activates protein kinase C (PKC), which in turn tales part in insulin secretion [35]. The effect of fatty acids on pancreatic islet insulin release depends mainly on degree and time of exposure. Circulating low levels of free fatty acids in the range of physiologic postprandial values actually aids in enhancing glucose-induced insulin secretion. However, excessive accumulation of lipids within islets impairs insulin secretion [36].
\nAt individual concentrations amino acids found in physiological concentrations are poor insulin secretagogues. Some combinations of amino acids at physiological concentrations are capable of enhancing GSIS [37], like that of, glutamine cannot stimulate insulin secretion or enhance GSIS alone, but in combination with leucine, glutamine is capable of stimulating insulin secretion from β-cells and enhancing GSIS [38]. Leucine activates glutamate dehydrogenase, and glutamate dehydrogenase can convert glutamate to α-ketoglutarate, leading to production of ATP and stimulating insulin secretion [37]. Two important incretin hormones secreted from K-cells and L-cells in the gastrointestinal tract, Glucose dependent insulinotropic peptide (GIP) and glucagon-like peptide-1 (GLP-1), are stimulated to be secreted after ingestion of nutrients like glucose and amino acids. These hormone levels rise in the circulation after feeding food rich in protein and carbohydrates. Then they directly trigger insulin secretion from β-cells by binding to their specific cell-surface receptors, hence enhancing GSIS [39, 40, 41].
\nGLP-1 is an incretin hormone secreted from small intestinal L-cells along with GIP when the nutrient content in blood is high generally after ingestion [42, 43]. Nutrient load from oral route triggers more insulin secretion than intravenous nutrient load [44]. GLP1-agonists and analogues are already used as an effective therapy for type 2 diabetes that are safe due to the glucose dependent effect on the insulin secretion and large randomized clinical trials proved their additional cardiovascular benefits [45]. GLP-1 acts upon β-cells due to the presence of GLP-1 receptor (GLP-1R). Activation of GLP-1R leads to activation of adenylyl cyclase, which in turn generates cAMP. Elevated level of cAMP in the cytosol enhances GSIS. Hence GLP-1 secretion is dependent on high blood glucose levels [45, 46].
\nLeptin, secreted from adipocytes, regulates function of insulin upon the glucose storing fat and liver cells [47, 48]. However, in absence of leptin, hyperinsulinemia leads to drop in blood glucose levels [47, 49]. The inhibitory action of leptin has been well known in clonal β-cells [50], cultured rodent islets [51], perfused rodent pancreas [50, 52], human islets [51, 53, 54] and mice islets [51]. Leptin inhibits insulin secretion by antagonizing the action of elevated intracellular cAMP [55]. 3-isobutyl-1-methylxanthine (IBMX) induces leptin, elevating cAMP content by inhibiting phosphodiesterases (PDEs) [56], the enzymes which catalyze hydrolysis of cAMP. GLP-1-induced insulin secretion is also inhibited by leptin, and GLP-1 which augments insulin secretion by activation of the cAMP signaling pathways [52].
\nIn the “classical” mechanism of action of estrogen, the estrogen molecules diffuse into cell and bind to the estrogen receptor ER located in the nucleus. Rapid or “nongenomic” effects of estrogen are thought to occur through the ER located in or adjacent to the plasma membrane and may require presence of “adaptor” proteins, which target the ER to the membrane. Activation of the membrane ER leads to a rapid change in cellular signaling molecules and stimulation of kinase activity, which in turn may affect transcription [57].
\nβ-cells are not general estrogen targets but the presence of estrogen receptor in islets makes the effect of 17β-estradiol on β-cells noteworthy [58, 59]. 17β-estradiol enhances insulin secretion from β-cells [60] and in humans, it is known to increase insulin secretion in postmenopausal women [61, 62], thus it augments glucose-stimulated insulin secretion (GSIS) [63]. Two types of are present in β-cells: (1) the estrogen receptors in the nucleus, i.e., nuclear ERs (ERα and ERβ) and (2) the estrogen receptors in the membrane, i.e., the membrane ER (ERγ) [64]. 17β-estradiol significantly decreases activity of KATP channel [60], causing membrane depolarization and opening of voltage-gated Ca2+ channels, thereby potentiating glucose-induced intracellular [Ca2+] oscillations, in a reversible manner.
\nMelatonin, a hormone secreted by pineal gland, helps in maintaining circadian rhythm and biological clock [65]. However, melatonin receptors are found on clonal β-cells [66, 67] and human islets [68]. Melatonin shows both stimulatory [69] and inhibitory effects [70, 71], as well as neutral effects [72] on insulin section. However a decent number of reports have been found in literature about the inhibitory effect of melatonin in clonal β-cells [66, 68, 69, 73]. Melatonin inhibits glucose- and KCl-stimulated insulin secretion in rat islets [74]. Long term melatonin administration enhances hyperinsulinemia in vivo [75]. The signaling pathway of melatonin shows that melatonin receptor is coupled to Gi, which inhibits G protein [76]. Melatonin mediates stimulatory effect on insulin secretion through its receptor MTNR1A, by activation of Gq/11 which provokes release of IP3 by activating PLC-ε to augment insulin secretion [69, 77, 78].
\nGrowth hormone (GH) stimulates production of insulin-like growth factor-I (IGF-I) and its binding proteins [79]. Human IGF1 and IGF2 show high sequence similarity with insulin. Insulin receptor (IR) has two isoforms, IRA and IRB. IRB only binds insulin with high affinity while IRA binds both insulin and IGF2 with equal affinity. The IGF1 receptor (IGF1R) has high affinity towards both IGF1 and IGF2 but it binds insulin with very low affinity. According to the conventional view regarding the actions of insulin and IGF-1 in mammals, insulin mediates mainly a metabolic response, and IGF-1 mediates growth promoting effects in vivo [80]. Recombinant human IGF-I decreases serum levels of insulin and C-peptide in human [81]. IGF-1 also suppresses insulin secretion in isolated rat islets [82]. This inhibitory activity of growth hormone is mediated through PDE3B activation [83], which is responsible for breaking down cAMP in β-cells.
\nAdrenergic drugs (epinephrine, norepinephrine and isoproterenol) are known to inhibit insulin secretion by binding to alpha receptors present in rat pancreas. On the other hand cholinergic drugs (acetylcholine and carbamylcholine) stimulate insulin secretion but this effect is suppressed by simultaneous addition of atropine. Thus the autonomic nervous system regulates insulin secretion under physiological conditions [84] (Figure 2).
\nHormonal and nutrient regulation of insulin secretion [23, 26, 27, 32, 33, 34, 35, 45, 46, 55, 57, 60, 64, 72].
SIRT1, mammalian sirtuin homolog, plays a key role in energy homeostasis and extends a cell lifespan by calorie restriction [85]. Glucose metabolism is tightly coupled to the regulation of insulin secretion and β-cell function [86]. Till now there are two reports showing SIRT1 positively regulates glucose-stimulated insulin secretion in pancreatic β-cells [87, 88]. In β-cells, FoxO1 is constitutively phosphorylated in cytoplasm, and activates insulin receptor signaling [89]. Accumulation of FoxO1 in the nucleus of insulin-secreting cells is triggered by palmitate during induction of lipotoxicity and impairs insulin secretion [90, 91]. Increased expression of SIRT1 in pancreatic β cells in mice improves glucose tolerance by enhancing insulin secretion [87]; deletion of SIRT1 can impair glucose-stimulated insulin secretion [88]. In both these reports, SIRT1 enhances insulin secretion by transcriptional repression of uncoupling protein 2 (UCP2) [92]. Activation of SIRT1 gives protection from high-fat-induced obesity and insulin resistance [92, 93, 94], and slight overexpression of SIRT1 has a protective role from high-fat induced glucose intolerance [95, 96, 97]. If SIRT1 is inhibited then insulin promoter activity is suppressed, insulin regulatory genes such as v-maf musculoaponeurotic fibrosarcoma oncogene homolog A (MafA) and NK6 homeodomain 1 (NKX6.1) mRNA expressions are down regulated leading to decreased insulin secretion. On the contrary, activation or overexpression of SIRT1 antagonizes reduced insulin transcriptional activity by exerting negative effect on pancreatic and duodenal homeobox 1 (PDX1)-stimulated insulin promoter activity and also abolishes forkhead box O1 protein (FOXO1)-insulin transcriptional activity [98].
\nPPAR-γ regulates the major β cell genes involved in glucose sensing, insulin secretion and insulin gene transcription and protects from glucose, lipid, cytokine and islet amyloid polypeptide (lAPP)-induced stress pathways [99]. PPAR-γ is a member of nuclear hormone receptor superfamily of ligand-activated transcription factors and TZDs are oral agents that are high-affinity activators of PPAR-γ [100]. PPARγ ablation protects mice from high fat diet induced insulin resistance [101] and isolated islets from these mice show blunted TZD response towards GSIS [102]. Mice with PPAR-γ ablated pancreas show glucose intolerance at baseline with downregulated Pdx-1 and GLUT2 expression in their isolated islets [103]. Chronic high glucose can decrease PPAR-γ mRNA levels in mouse islets [104]. PPAR-γ is upregulated after 60% pancreatectomy procedure in rats changing to pro differentiation state from proliferative state [105]. Promoters of GLUT2 and glucokinase have functional PPREs that bind PPAR-γ/RXRα heterodimer, and lead to transcriptional upregulation of these genes in β cell [106, 107]. The expression of these genes is impaired in diabetic rodent models [108, 109].
\nPPARγ agonists modulate IAPP-induced ER stress [110]. The islet-specific KO of the ATP-binding membrane cassette transporter protein A1 (ABCA1) and PPAR-γ KO model both show increased intra-islet triglyceride accumulation and lowered GSIS [101, 111]. Rosiglitazone restores GSIS and decreases apoptosis in isolated human lipotoxic islets with a reduction in intra-islet triglyceride accumulation and reduced inducible nitric oxide synthase (iNOS) expression [112, 113]. PPAR-γ agonists also inhibit cytokine-induced activation of JNK in insulinoma cell lines [114]. PPAR-γ agonists have been shown to increase AKT phosphorylation in the setting of both IAPP-and lipid-inducted toxicity. These effects were blocked by PI3 kinase inhibitors and associated with increased levels of insulin receptor substrate 2 (IRS2) proteins [115].
\nActivation of PPAR-γ inhibits IL-1β and IFN-γ stimulated nuclear translocation of p65 subunit of NF-ΚB and DNA binding activity leading to reduced inducible nitric oxide synthase and cyclooxygenase-2 expression [116].
\nPPAR-γ activation also increases intracellular calcium mobilization, insulin secretion, and β-cell gene expression through GPR40 and GLUT2 gene upregulation [117]. Thus PPAR-γ agonists not only improve insulin sensitivity in the target tissues, but also act within the β-cells.
\nWnt signaling stimulates β-cell proliferation, specifically Wnt3a promotes expression of Pitx2, a direct target of Wnt signaling, and Cyclin D2, an essential regulator of cell cycle progression [118]. Single nucleotide polymorphisms (SNPs) in TCF7L2 are linked to etiology of T2D [119]. Expression of three Tcf genes (Tcf7, Tcf7l1, Tcf7l2) in pancreas is reduced by treatment with insulin or high fat diet feeding [120]. A significant elevation of TCF7L2 mRNA expression occurs in pancreatic islets along with impaired insulin secretion [121]. TCF7L2 depletion in isolated human or mouse pancreatic islets results in significant increased β-cell apoptosis and decreased proliferation with attenuated GSIS. Over-expression of TCF7L2 protects islets from glucose- and cytokine-mediated apoptosis [122]. These findings suggest that β-cell function and survival are positively regulated by the expression of Tcf7l2 in type 2 diabetes.
\nRapamycin, an mTORC1 complex inhibitor, reduces the number and proliferation of pancreatic and endocrine progenitors. Mice lacking mTOR in pancreatic progenitors suffer from hyperglycemia in neonates, hypoinsulinemia and pancreatic agenesis/hypoplasia with pancreas rudiments containing ductal structures lacking differentiated acinar and endocrine cells [123].
\nAMP-activated protein kinase (AMPK) is a controller of β-cell function. Inhibition of AMPK in β-cells by high glucose inversely correlates with activation of the mammalian Target of Rapamycin (mTOR) pathway. Glucose and amino acid sensing ability of AMPK is important in regulation of insulin secretion [124]. Rapamycin also induces fulminant diabetes by increasing insulin resistance and reducing-cell function and mass [125].
\nObesity induced by excess nutrient intake leads to the upregulation of mTORC1/S6K1 signaling in insulin-sensitive tissues, including β-cells [126, 127, 128]. mTORC1 activation play an initial role in adaptation to nutrient excess and obesity, but chronic and persistent hyperactivation could lead to development of insulin resistance by a negative feedback loop on IRS signaling [129].
\nMonocyte chemoattractant protein-1 (MCP-1) a chemokine that regulates migration and infiltration of monocytes/macrophages, is constitutively present in normal human islet β-cells in the absence of an inflammatory infiltrate and plays a key role in monocyte recruitment [130]. NF-kappaB plays an important role for MCP-1 expression in β-cells [131]. MCP-1 also induces amylin expression through ERK1/2/JNK-AP1 and NF-κB related signaling pathways independent of CCR2. Amylin upregulation by MCP-1 may contribute to elevation of plasma amylin in obesity and insulin resistance [132].
\nThe Keap1-Nrf2 signaling plays an important role in oxidative stress response and metabolism. Nrf2 prevents reactive oxygen species ROS mediated damage in pancreatic β-cells [133]. β-cells have low expression levels of antioxidant enzymes, making them susceptible to damage caused by ROS. GLP-1 effectively inhibits oxidative stress and cell death of β-cells induced by the pro-oxidant tert-butyl hydroperoxide (tert-BOOH) [134]. NOX activation through Src signaling plays an important role in ROS overproduction and impaired GSIS caused by lipotoxicity [135].
\nEpidermal growth factor receptors are crucial regulators of β-cell proliferation and β-cell mass regulation. Partial tissue-specific attenuation of EGFR signaling in islets leads to significantly reduced beta-cell proliferation [136]. Phosphorylation of ribosomal S6 kinase, a mammalian target of rapamycin (mTOR) target, is upregulated in islets from glucose and interleukin injected 6-month-old rats. β-cell mass expansion occurs in presence of chronic nutrient excess EGFR signaling, mTOR activation, and FOXM1-mediated cell proliferation [137].
\nIn pancreatic β-cells, the endoplasmic reticulum (ER) is an important cellular compartment involved in insulin biosynthesis. ER stress elicits a signaling cascade known as the unfolded protein response (UPR) which regulates both function and survivability of β-cells [138]. Chronic high glucose leads to insulin mRNA degradation by IRE1α activation, profuse XBP-1 splicing, and induction of pro-apoptotic effectors, such as Jun N-terminal kinase (JNK) and C/EBP homologous protein (CHOP), causing β-cell dysfunction and death [139, 140, 141, 142]. Free fatty acids (FFAs) and inflammatory cytokines also induce ER stress in β-cells through upregulation of the proapoptotic effector CHOP, and JNK and caspase-12 activation by UPR [143, 144, 145, 146].
\nER stress, oxidative stress and high glucose concentrations activates NLRP3 inflammasome leading to interleukin (IL)-1β production and caspase-1 dependent pyroptosis. Whether IL-1β or intrinsic NLRP3 inflammasome activation contributes to β-cell death is disputed [147].
\nThe Nlrp3 inflammasome plays important role in obesity-induced insulin resistance and β-cell failure. Endocannabinoids contribute to insulin resistance through activation of peripheral CB1 receptors (CB1Rs) promoting β-cell failure [148]. NLRP3-knockout mice showed improved glucose profiles after a high-fat diet, due to attenuated IL-1β release from islet cells. Hyperglycemia-induced IL-1β release leads to increased ROS, dissociation of TXNIP from thioredoxin and its binding to NLRP3 and activation of NLRP3 [149].
\nToll-like receptor 4 (TLR4), a pattern recognition receptor, is a crucial element in the triggering of innate immunity, which binds to pathogen-associated molecules such as Lipopolysaccharide (LPS), and initiates a cascade of pro-inflammatory events [150]. TLR4 is also known to occur in pancreatic β-cells but its function is yet to be clearly established. β-cells respond to palmitate via TLR4/MyD88 pathway and produce chemokines that recruit M1-type proinflammatory monocytes/macrophages to the islets [151]. High fat diet-induced obesity stimulates TLR4 up-regulation in pancreatic β-cells, and lead to the recruitment of macrophage into pancreatic islet, which finally results in pancreatic β-cell dysfunction [152].
\nFetuin-A, a secreted glycoprotein, can promote lipotoxicity in β-cells through the TLR4-JNK-NF-κB signaling pathway [153]. Later it was also discovered that pancreatic β-cells are capable of secreting fetuin-A under free fatty acid stimulation which ultimately leads to inflammation [154].
\nMedium- to long-chain fatty acids activate FFAR1/GPR40 and it is predominantly coupled to Gαq which signals through PLC-mediated hydrolysis of membrane phospholipids leading to the formation of IP3 and DAG [155, 156]. Glucose tolerance and insulin secretion is impaired in mice due to β-cell-specific inactivation of the genes encoding the G protein α-subunits Gαq and Gα11. Thus, Gq/G11-mediated signaling pathway mediates insulin secretion by glucose stimulation [157] (Figure 3).
\nVarious signaling pathways regulating insulin secretion signaling [90, 91, 98, 99, 106, 107, 120, 129, 132, 134, 135, 137, 139, 140, 141, 142, 153, 154, 155, 156, 157].
In conclusion, insulin secretion is stimulated by glucose, free fatty acids and amino acids after their breakdown in gut following ingestion. Glucose potentiates KATP channel-dependent insulin secretion. Free fatty acids result in insulin secretion from β-cells through free fatty acid receptor (FFAR)-1. Under incretin stimulation the amino acids trigger insulin secretion by binding to their cell surface receptors. Hormones like GLP-1 and estrogen stimulate insulin secretion, melatonin has both stimulatory and inhibitory effect and leptin and growth hormone have only inhibitory effects upon insulin secretion. Discussing about the various signaling pathways, mainly Wnt, G-proteins, EGFR, mTOR, SIRT1, PPARγ mediate increased insulin secretion, β-cell proliferation and improved GSIS in presence of nutrients, while in case of excessive nutrient load TLR4, MCP1, inflammasomes and Nrf2 impairs insulin secretion and conduces β-cell death. These excess of nutrients are the key players behind glucotoxicity and lipotoxicity, which ultimately lead to compensatory insulin secretion, β-cell mass expansion initially and β-cell death under chronic nutrients overload. Our major concern should be leading a healthy lifestyle, active routine, regular exercise, balanced diet and constant awareness about the incidence of type 2 diabetes, for eradication and curing of the disease to some extent.
\nAM is thankful to the Science & Engineering Research Board (SERB), Department of Science & Technology, Govt. of India, for her JRF fellowship (Grant No. ECR/2017/001028). DC thankful DBT for JRF. SD thanks UGC, New Delhi for SRF. The authors are thankful to Dr. Rakesh Kundu and Dr. Sandip Mukherjee for their technical assistance and constant encouragement.
\nThe authors declare no conflict of interest.
The authors thank to the Head of the Department of Zoology, for providing the assistance in their research work.
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