Special Issue "Tissue and Organ Regeneration"

Guest Editor
Prof. Dr. Georg Breier
Department of Pathology, University Hospital, Faculty of Medicine Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307 Dresden, Germany
Website: http://tu-dresden.de/med
E-Mail: Georg.Breier@uniklinikum-dresden.de

Submission

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Type of Paper: Review
Title: Effects of Guanosine on Regeneration of Central Nervous System
Authors: Shucui Jiang ¹, Caixin Su ¹, Michel Rathbone ², Patrizia Ballerini ³, Patrizia Di Iorio ³ and Francesco Caciagli ³
Affiliations: ¹ Department of surgery (Neurosurgery, Neurobiology), Hamilton Neurorestorative Group, McMaster University, Canada; E-Mail: jiangs@mcmaster.ca;
² Department of medicine (Neurology, Neurobiochemistry), McMaster, Canada
³ Department of Biomedical Sciences, University of Chieti-Pescara, Chieti, Italy
Abstract: We discovered and others confirmed that the nucleoside guanosine and its base guanine are important intercellular signaling molecules, mediating cell growth, differentiation, survival, acting as neuromodulators, and promoting differentiation and outgrowth of nerve processes. Guanosine is neuroprotective and neurorestorative in various brain disorders. We recently discovered that guanosine stimulates proliferation of endogenous progenitor/stem cells in the adult mammalian nervous system following chronic disorders. In this review we will update the biological effects of guanosine on tissue regeneration in CNS and discuss some potential mechanisms through which guanosine exerts its beneficial effects including neurotrophic factors, enzyme regulation and receptor-mediated pathways.

Type of Paper: Review
Title: The Convergence of Microfluidics and Tissue Engineering for the Development of in Vitro Cancer Model
Authors: Sara Budar, Xiaochuan Yang and Hongjun Wang
Affiliation: Chemical Biology & Biomedical Engineering, Stevens Institute of Technology, Hoboken, NJ 07030, USA; E-Mail: Hongjun.Wang@stevens.edu
Abstract: In search for various treatments of cancers, the establishment of an efficient tumor model, maximally capturing the pathophysiological features of counterparts in vivo, becomes extremely crucial to facilitate the translation of research findings to clinical applications. Compared to the 2D culture model on a planar surface, mouse-bearing tumor model is more close to in vivo circumstances. However, the associated high cost and high variation in treatment outcome can significantly decelerate the evaluation process. 3D in vitro tissue models have been considered promising to bridge the gap between 2D in vitro culture and the in vivo animal model. This review summarises recent progress in creation of various cancer models using a tissue-engineering strategy, and emphases are particularly made to address the potential utilization of microfluidic devices for such endeavor.

Type of Paper: Review
Title: Signals and Cells Involved in Regulating Appropriate Liver Regeneration
Authors: Liang-I Kang and George K. Michalopoulos
Affiliation: Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; E-Mails: lik19@pitt.edu (L.I.K.); michalopoulosgk@upmc.edu (G.K.M.)
Abstract: Liver regeneration is a complex phenomenon aimed to maintain a constant liver mass in the event of injury resulting in loss of hepatic parenchyma. Partial hepatectomy is followed by a series of events involving multiple signaling pathways controlled by mitogenic growth factors (HGF, EGF) and their receptors (MET and EGFR). In addition multiple cytokines and other signaling molecules contribute to the orchestration of a signal which drives hepatocytes into DNA synthesis. The other cell types of the liver receive and transmit to hepatocytes complex signals so that, in the end of the regenerative process, complete hepatic tissue is assembled and regeneration is terminated at the proper time and at the right liver size. If hepatocytes failed to participate in this process, the biliary compartment is mobilized to generate populations of progenitor cells which trans-differentiate hepatocytes and restore liver size.

Type of Paper: Article
Title: A Preliminary Evaluation of Lyophilized Gelatin Gel Scaffolds Enhanced with Platelet-rich Plasma, Hydroxyapatite, and Chitin Whiskers for Bone Regeneration
Authors: Scott A. Sell ^{1, 2}, Isaac A. Rodriguez ², Jennifer M. McCool ², Andrew J. Spence ³, Matthew J. Beckman ⁴ and Gary L. Bowlin ²
Affiliations: ¹ Physical Medicine & Rehabilitation Service, Hunter Holmes McGuire VA Medical Center, Richmond, VA, USA; E-Mail: s2sasell@mymail.vcu.edu
² Department of Biomedical Engineering, Virginia Commonwealth University, Richmond, VA, USA
³ Department of Biology, Virginia Commonwealth University, Richmond, VA, USA
⁴ Department of Pharmacotherapy and Outcomes Science, Virginia Commonwealth University, Richmond, VA, USA
Abstract: This article will focus on the use of lyophilized gelatin gels to serve as bone regeneration templates. Gels will be modified through the addition of platelet-rich plasma (PRP), hydroxyapatite, and chitin whiskers. PRP therapy is an emerging practice that has proven effective in a number of clinical applications, including enhancing bone repair. The inclusion of lyophilized PRP in our gelatin scaffolds is intended to significantly enhance scaffold bioactivity, while the addition of hydroxyapatite and chitin whiskers are anticipated to increase scaffold strength. Scaffolds will be evaluated in vitro with respect to compressive strength, mass loss/degradation, protein release, and cellular interaction.

Type of Paper: Review
Title: Bone Marrow-derived Mesenchymal Stromal Cells for Muscle Repair/Regeneration: Novel Concepts and Therapeutic Implications
Authors: Chiara Sassoli, Sandra Zecchi-Orlandini and Lucia Formigli
Affiliation: Dept. of Anatomy, Histology and Forensic Medicine, University of Florence, Largo Brambilla 3, 50134 Florence, Italy; E-Mails: csassoli@unifi.it (C.S.); zecchi@unifi.it (S. Z.O.); formigli@unifi.it (L.F.)
Abstract: Bone marrow-derived multipotent mesenchymal stromal cells (MSCs) represent a leading cell candidate in tissue engineering and regenerative medicine. These cells can be easily isolated,  expanded in vitro and are capable of providing significant functional benefits after implantation in the damaged tissues, including skeletal and cardiac muscle. Despite their plasticity, the participation of MSCs to new muscle fiber formation is controversial and emerging evidence indicates that their therapeutic effects occur without evidence of long-term tissue engraftment and involve the paracrine secretion of cytokines and growth factors with multiple effects on the injured tissue, including modulation of inflammation and immune reaction, positive ECM remodeling, angiogenesis and protection from apoptosis. Recently, a new role for MSCs in the stimulation of muscle progenitor cells proliferation has been demonstrated, suggesting the potential ability of these cells to influence the fate of local stem cells and augment the endogenous repair of the damaged tissues.

Type of Paper: Review
Title: Regenerative Effect Exerted by Mesenchymal Stem Cells: Contribution of a Novel Type of Pluripotent Stem Cells, Muse Cells, that Reside in Mesenchymal Tissues
Author: Mari Dezawa
Affiliation: Department of Stem Cell Biology and Histology & Department of Anatomy and Anthropology, Tohoku Univeristy Graduate School of Medicine; E-Mail: mdezawa@med.tohoku.ac.jp
Abstract: Because of easy accessibility and safety, mesenchymal stem cells (MSCs) are already applied to human aiming for tissue regeneration. MSCs are known to have multiple functions, but their entity still remains an enigma; they are known to exert trophic effect, immunomodulation and anti-apoptotic effect but since MSCs are generally harvested from mesenchymal tissues such as bone marrow, adipose tissue or umbilical cord, MSCs are in fact crude cell population and thus heterogenous. Therefore, cells responsible for each effect has not been clarified. The most interesting property of MSCs is that, even though they are adult stem cells, they differentiate into a broad spectrum of cells that crosses the oligolineage boundaries between mesodermal and ectodermal or endodermal lineages. Recently, a novel type of pluripotent stem cells were found in adult human mesenchymal tissues that may explain broad spectrum of differentiation and cell replenishment in multiple organs when transplanted. In this review, we will introduce updated studies regarding regenerative effect of MSCs and discuss about its possibility in regenerative medicine.

Type of Paper: Review
Title: Decellularized Tendon Extracellular Matrix - a Valuable Approach for Tendon Reconstruction?
Authors: Gundula Schulze-Tanzil, Wolfgang Ertel and Anke Lohan
Affiliation: Charité-Universitätsmedizin Berlin, Campus Benjamin Franklin, Department of Orthopaedic, Trauma and Reconstructive Surgery, Garystrasse 5, 14195 Berlin, Germany; E-Mail: gundula.schulze-tanzil@charite.de
Abstract: Tendon healing is generally time consuming and often leads to a functionally altered reparative tissue. To use degradable scaffolds for tendon reconstruction remains still a compromise in view of the required high mechanical strength of tendon. Regenerative approaches based on natural decellularized allo- or xenogenic tendon extracellular matrix (ECM) currently attract increasing interest. This ECM combines the advantages of its intrinsic mechanical competence with that of providing tenogenic stimuli for immigrating cells mediated e.g. by the growth factors and other mediators bound within the natural ECM. A major restriction for its therapeutically application is the mainly cell-associated immunogenicity of xenogenic or allogenic tissues and the risk of disease transmission. A survey of approaches for tendon reconstruction using cell-freed ECM will be presented here, whereby the problems associated with tendon ECM decellularization procedures, success of various recellularization strategies, suitable cell types applied, will be thoroughly discussed. Encouraging in vivo results using cell-free ECM e.g. in rabbit models have already been reported. However, in comparison to native tendon, in reseeded tendon ECM the cells remain mostly inhomogeneously distributed and do not align. Hence, future work should focus on optimization of tendon ECM decellularization and cell recolonization strategies to restore tendon functionality.

Type of Paper: Review
Title: High Mobility Group Box Protein-1 in Wound Repair
Authors: Elia Ranzato ¹, Simona Martinotti ¹, Marco Pedrazzi ², Mauro Patrone ¹
Affiliations: ¹ Dipartimento di Scienze e Innovazione Tecnologica, DiSIT, University of Piemonte Orientale “Amedeo Avogadro”, viale T. Michel 11, 15121 Alessandria, Italy; E-Mails:elia.ranzato@mfn.unipmn.it (E.R.) ; simona.martinotti@unipmn.it (S.M.); mauro.patrone@mfn.unipmn.it (M.P.)
² Department of Experimental Medicine (DIMES)-Biochemistry Section, and Center of Excellence for Biomedical Research (CEBR), University of Genoa, Viale Benedetto XV, 1-16132 Genoa, Italy; E-Mail:marco.pedrazzi@unige.it
Abstract: HMGB1, a member of highly conserved non-histone DNA binding protein family, has been studied as transcription factor and growth factor. Secreted extracellularly by activated monocytes and macrophages or passively released by necrotic or damaged cells, extracellular HMGB1 is a potent mediator of inflammation. Extracellular HMGB1 has apparently contrasting biological actions: it sustains inflammation (with the possible establishment of autoimmunity or of self-maintaining tissue damage), but it also activates and recruits stem cells, boosting tissue repair. 
Here, we focus on the role of HMGB1 in physiological and pathological responses, the mechanisms by which it contributes to tissue repair and therapeutic strategies base on targeting HMGB1.

Type of Paper: Review 
Title: Cell and Gene Therapy Approaches for Cardiac Vascularization
Authors: Ludovic Melly ^1,2, Stefano Boccardo ³, Andrea Banfi ¹, Anna Marsano ¹
Affiliations: ¹ Cell and Gene Therapy, Department of Biomedicine and Department of Surgery, Basel University Hospital, Switzerland
² Cardiac Surgery, Department of Surgery, Basel University Hospital, Swizterland
³ Department of Robotics, Brain & Cognitive Sciences, Italian Institute of Technology, Genova, Italy; E-Mail: lmelly@uhbs.ch
Abstract: Despite encouraging preclinical results for therapeutic angiogenesis in cardiac ischemia, a suitable approach providing sustained, safe and efficacious vascular growth in the heart is still lacking. Vascular Endothelial Growth Factor (VEGF) is the master regulator of angiogenesis, but it also can easily induce aberrant and dysfunctional vascular growth if its expression is not tightly controlled. Control of the released level around each cell in vivo and its distribution in tissue are critical to induce stable and functional vessels for therapeutic angiogenesis. The present review discusses the limitations and perspectives of VEGF gene therapy and of different cell-based approaches for the implementation of therapeutic angiogenesis in the treatment of cardiac ischemia.

Type of Paper: Article
Title: Non-tumorigenic Neuronal Precursor Cell Lines Generated from Pluripotent Stem Cells can be Efficiently Differentiated into Dopaminergic Neurons
Authors: M. Chih Liao ¹, C. Trenkwalder ², W. Paulus ², R. Dressel 3 and A. Mansouri ^1,2
Affiliations: ¹ Max-Planck Institute for Biophysical Chemistry, Department of Molecular Cell Biology, Am Fassberg 11, 37077 Göttingen, Germany; E-Mail: amansou@gwdg.de
² University of Göttingen, Department of Neurophysiology, Robert-Koch strasse 40, 37075 Göttingen; 3. University of Göttingen, Department of Cellular and Molecular Immunology, Humboldtallee 34, 37073 Göttingen, Germany
Abstract: The derivation of human embryonic stem cells (hES) has opened new avenues for assessing novel approaches for future stem cell-based therapies. This has been further stimulated by recently developed induced pluripotent stem cells (iPS) from fibroblasts or other human adult tissues. The most stringent test to demonstrate pluripotency of human stem cell lines is the teratoma growth assay in immunodeficient mice. However, teratoma formation remains a major problem for future therapies using pluripotent stem cells as source of cellular transplants. We have developed a protocol to generate neural precursor cell lines from these pluripotent stem cells. We show that neural progenitor cell lines are able to differentiate into dopaminergic neurons in vitro and do not form teratomas in immunodeficient mice.

Type of Paper: Review
Title: Stem Cells and Tissue Renewal
Author: Christian Drapeau et al.
Affiliation: Stemtech International, California, USA; E-Mail: cdrapeau@stemtechmail.com
Abstract: Recent advances in stem cell research has revealed an underlying mechanism of tissue renewal based on bone marrow-derived stem cells and a process of tissue turnover that significantly exceeds previous understanding. The turnover of many tissues and organs is such that tissue renewal is essential in order to maintain adequate organ function, to the point that a reduction in the natural process of tissue repair could be an underlying mechanism of disease formation. Indeed, a reduced number of circulating stem cells or otherwise impaired stem cell function has already been linked with the development of a series of generative diseases, including cardiomyopathy, kidney failure, diabetes, atherosclerosis, Alzheimer’s disease and even erectile dysfunction. In light of these recent observations, clinical approaches that support stem cell function could serve a significant tools for prevention.

Type of Paper: Review
Title: Mesenchymal Stem Cells from Different Sources and their Potential for Clinical Use
Authors: Tim Hatlapatka ¹, Anne Neumann ¹ , Simone Hennebichler ² , Christian Gabriel ² and Cornelia Kasper ¹
Affiliations: ¹ University of Natural Resources and Life Sciences BOKU, Department for Biotechnology, Muthgasse 18, A-1190 Vienna, Austria; E-Mails: tim.hatlapatka@boku.ac.at (T.H.); anne.neumann@boku.ac.at (A.N.); cornelia.kasper@boku.ac.at (C.K.)
² Österreichisches Rotes Kreuz, Blutzentrale Linz (Austrian Cluster for Tissue Regeneration), Krankenhausstraße 7, 4017 Linz, Austria; E-Mails: simone.hennebichler@o.roteskreuz.at (S.H.); christian.gabriel@o.roteskreuz.at (C.G.)
Abstract: Mesenchymal stem or stromal cells (MSCs) have proven to offer great promise for cell-based therapies and tissue engineering applications as these cells are capable for extensive self-renewal and display a multilineage differentiation potential. Furthermore, MSC were shown to exhibit immunomodulatory properties and display supportive functions through parakrine effects. Besides the bone marrow (BM), today still the most common source of MSC, the cells were found to be present in a variety of postnatal and extraembryonic tissues and organs as well as in a large variety of fetal tissues. Over the last decade the human umbilical cord and other birth- associated tissues have been found to be a rich and valuable source of MSC which are bio-equivalent to BM-MSC. Since these tissues are discarded after birth, the cells are easily accessible without ethical concerns.

Type of Paper: Review
Title: Heart Regeneration Using Stem Cells
Author: Nanako Kawaguchi
Affiliation: Department of Pediatric Cardiology, Tokyo Women’s Medical University, Tokyo, Japan; E-Mail: nanako.res@gmail.com
Abstract: The heart has been thought to be a terminal differentiated organ, so that once cardiomyocytes dye, no recovery would be made to replace those dead cells. However, around a decade ago, the concept of stem cells was proposed that differentiate into cardiomyocyte to keep functioning. I would like to address to cardiomyocyte differentiation and the possibility of the role of stem cells in a heart.

Type of Paper: Article
Title: The Potential for Resident Lung Mesenchymal Stem Cells to Promote Functional Tissue Regeneration: Understanding Microenvironmental Cues
Authors: Robert F. Foronjy ¹ and Susan M Majka ²
Affiliations: ¹ Department of Medicine, St. Luke’s Roosevelt Health Sciences Center, Antenucci Building, 432 West 58th Street, Room 311, New York, NY 10019, USA; E-Mail:robertforonjy@yahoo.com
² Department of Medicine, Vanderbilt University, 1161 21st Ave S, T1218 MCN, Nashville, TN 37232, USA; E-Mail: susan.m.majka@Vanderbilt.edu
Abstract: Tissue resident mesenchymal stem cells (MSCs) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Bone marrow derived mesenchymal stem cells (BM-MSCs) and endothelial progenitor cells (EPC) are currently being considered and tested in clinical trials as a potential therapy in patients with such inflammatory lung diseases including, but not limited to, chronic lung disease, pulmonary arterial hypertension (PAH), pulmonary fibrosis (PF), chronic obstructive pulmonary disease (COPD) / emphysema and asthma. However, our current understanding of tissue resident lung MSCs remains limited. This review addresses how environmental cues impact on the phenotype and function of this endogenous stem cell pool. In addition, it examines how these local factors influence the efficacy of cell-based treatments for lung diseases.