The field of preclinical models is a very vast arena, in which finding connections among groups acting in apparently very distant research areas can sometimes prove challenging [...

Attanasio C.

Sangiovanni M.

English

Archivio della ricerca - Università degli studi di Napoli Federico II

Journal ofClinical MedicineEditorialPreclinical Models: Boosting Synergies forImproved TranslationChiara Attanasio 1,2,3,* and Mara Sangiovanni 41 Department of Veterinary Medicine and Animal Productions, University of Naples Federico II,80137 Napoli, Italy2 Center for Advanced Biomaterials for Health Care—Istituto Italiano di Tecnologia, 80125 Napoli, Italy3 Interdepartmental Center for Research in Biomaterials (CRIB) University of Naples Federico II,80125 Napoli, Italy4 Stazione Zoologica “Anton Dohrn”, 80122 Napoli, Italy; mara.sangiovanni@szn.it* Correspondence: chiara.attanasio@unina.itReceived: 24 March 2020; Accepted: 1 April 2020; Published: 3 April 2020The field of preclinical models is a very vast arena, in which finding connections among groupsacting in apparently very distant research areas can sometimes prove challenging. An osmosis ofmindset and competencies (methodologies, techniques, models), along with a comparison of differentstandpoints, is always an opportunity to reflect on where one’s work stands in a wider scenario.The goal of this Special Issue is to collect information, and ultimately share ideas and foster debateabout different approaches to translational model research. The eleven papers composing this issuewill be of interest to researchers looking for an update of the currently heterogeneous panorama ofpreclinical models and to those in search of inspiring ideas in the field.Figure 1 shows a visual representation of the connections among the papers here presented. Eachcolored ribbon relates a paper with a topic. It is immediately apparent how many topics are addressedand how many relationships exist among the different research areas. Multidisciplinarity, which isintrinsic to the very nature of preclinical models, emerges at first sight as a relevant feature.Out of eleven papers, six are based on animal models [1–6], highlighting that these models stillplay a crucial role in translational medicine, even in a historical moment in which the need to findalternative methodologies is increasingly pressing.In this context, the issue raised by some authors about the translational validity of a certain animalmodel, in this specific case the Reeler mouse, is very timely. Central to the debate is the rare occurrenceof the very conditions for which mice homozygous for the Reeler mutation have been created, and theobjective difficulty of fully validating the mice expressing the heterozygous genotype as a translationalmodel for more frequent diseases such as autism and schizophrenia [2].After all, animal models are often suspended “halfway” between being widely accepted as goodtools for basic research and being recognized for their translational potential. Therefore, this issueshould always be considered when somebody, whether experimenter or modeler, decides to workwith them. In this regard, one paper focuses on the improvement of cellular and animal models ofchondrosarcoma. The authors [4] provide four cell lines, displaying tumorigenic and invasive featuressuitable to be used as valuable alternatives to veteran endless passaged cell lines. They also detail thegenetic drift that these cells underwent as an adaptive response to in vitro and in vivo expansion.J. Clin. Med. 2020, 9, 1011; doi:10.3390/jcm9041011 www.mdpi.com/journal/jcmJ. Clin. Med. 2020, 9, 1011 2 of 4J. Clin. Med. 2020, 9, x  2 of 4   Figure 1. A visual representation of the connections among the papers presented in this Special Issue. Several topics were defined by widening the keywords specified in each paper (colored sectors on the left side of the image). Papers (gray sectors on the right side of the image) are identified by the first author’s name. Colored ribbons connect papers with the topics treated. The figure was made with the Circos software [7]. Cancer, and more specifically the usage of nanoparticles (NP) both for multimodal imaging and as contrast agents (CAs), is the topic of a review [8] which highlights the advantages of using NP-based PET/MRI multimodal imaging in tumor diagnosis and characterization. Additionally, these nanosystems can be applied to theranostics in the very prominent scenario of personalized medicine. The authors point to multidisciplinarity as an essential requisite to deeply understand the possible applications and the underlying biomolecular processes of the targeted diseases. The centrality of interdisciplinary synergies is further highlighted in a paper [6] specifically focused on the high potential held by MRI imaging in translational oncology. By analyzing several disease models and cancer types, the authors present their approach to reduce the gap from preclinical applications to clinical practice. The “from bench to bedside” path is also the leitmotif of an article [9] addressing several issues related to the use of human-induced pluripotent stem cells (iPSC). More specifically, the paper analyses the potential of iPSC-endothelial cells in accelerating tissue regeneration and their suitability to enter progressively more clinical trials. The most represented research field in this Special Issue is tissue morphology [1–3,5] followed by tissue engineering [9–11] and neuroscience [1–3], with one article intercepting both these areas of expertise [12]. This latter work reports, indeed, a method to generate a three-dimensional neuronal system composed of cortical neurons and glial cells derived from iPSCs, suitable for drug screening and disease modeling. Good news from the field of skin regeneration: the work on bioengineered skin substitutes has been selected by the editorial board as the cover story of the issue of December 2019 (www.mdpi.com/2077-0383/8/12). The article, presented by a group active in the field of dermal substitutes [13] and three-dimensional tissue-like models [14], is focused on the analysis of the most Figure 1. A visual representation of the connections among the papers presented in this Special Issue.Several topics were defined by widening the keywords specified in each paper (colored sectors on theleft side of the image). Papers (gray sectors on the right side of the image) are identified by the firstauthor’s name. Colored ribbons connect papers with the topics treated. The figure was made with theCircos software [7].Cancer, and more specifically the usage of nanoparticles (NP) both for multimodal imagingand as contrast agents (CAs), is the topic of a review [8] which highlights the advantages of usingNP-based PET/MRI multimodal imaging in tumor diagnosis and characterization. Additionally, thesenanosystems can be applied to theranostics in the very prominent scenario of personalized medicine.The authors point to multidisciplinarity as an essential requisite to deeply understand the possibleapplications and the underlying biomolecular processes of the targeted diseases.The centrality of interdisciplinary synergies is further highlighted in a paper [6] specificallyfocused on the high potential held by MRI imaging in translational oncology. By analyzing severaldisease models and cancer types, the authors present their approach to reduce the gap from preclinicalapplications to clinical practice.The “from bench to bedside” path is also the leitmotif of an article [9] addressing several issuesrelated to the use of human-induced pluripotent stem cells (iPSC). More specifically, the paper analysesthe potential of iPSC-endothelial cells in accelerating tissue regeneration and their suitability to enterprogressively more clinical trials. The most represented research field in this Special Issue is tissuemorphology [1–3,5] followed by tissue engineering [9–11] and neuroscience [1–3], with one articleintercepting both these areas of expertise [12]. This latter work reports, indeed, a method to generate athree-dimensional neuronal system composed of cortical neurons and glial cells derived from iPSCs,suitable for drug screening and disease modeling.Good news from the field of skin regeneration: the work on bioengineered skin substitutes hasbeen selected by the editorial board as the cover story of the issue of December 2019 (www.mdpi.com/2077-0383/8/12). The article, presented by a group active in the field of dermal substitutes [13] andthree-dimensional tissue-like models [14], is focused on the analysis of the most modern strategies toJ. Clin. Med. 2020, 9, 1011 3 of 4overcome the scarring process and promote skin regeneration, by implanting an engineered dermiscapable of recapitulating the architecture and presenting molecular signals similarly to the nativedermis [10].The essential role of tissue-engineered constructs in mimicking extra-cellular matrix morphologyand function is also highlighted in another work, in which the authors analyze the most promisingfabrication technologies in the field. In particular, the paper reports the real effectiveness of the“bottom-up” approach for cell-free and cell-laden scaffolds in tissue and organ bioengineering [11].Passing to the fascinating and complex field of neuroscience, two original research articlescontributed to this Special Issue. It is worth noting how they both witness the increasing value ofthe short-lived African turquoise killifish Nothobranchius furzeri as an emerging vertebrate model inaging research. In particular, one paper describes, for the first time, the expression of neurotrophin-6 indifferent brain areas in both young and old animals [1], while the other one provides the first evidenceof nucleobindin-2/nesfatin-1 expression and its role as a food intake regulator in vertebrate aging [3].Finally, very high translational potential arises from a work proving the effectiveness of humanred blood cells to act as oxygen carriers for graft preservation in liver transplantation. In particular, thestudy is aimed at enhancing the potential of normothermic machine perfusion, a modern methodologyapplied to organ preservation [15]. In view of the crucial role of transplantation for patients withend-stage disease and the consequent increasing demand for the inclusion of marginal donors, newmethods to improve organ preservation and, eventually, induce graft repair are undoubtedly relevantto the clinical setting [5].An important contribution might come from in silico modeling, a field that has unexpectedly beenneglected in this Special Issue despite being a constitutive piece of the puzzle. In fact, in silico modelsprove to be useful at several stages of the process from research to clinical application, in a visionthat aims at a deep digital transformation of all the production steps. This might be accomplishedeither with data-driven approaches, such as in omics or materiomics simulations, or with mechanisticmodeling (e.g., bioreactors process) in tissue engineering [16]. Another interesting avenue is thedevelopment of in silico models capable of exploiting patient-specific data to build personalizedmedical treatments, such as three-dimensional mathematical models of tumors [17]. The urgency of anintegrated approach merging in vivo experiments and in silico representations to obtain more powerfuldescriptive and predictive models is also emerging: for instance, the integration of microfluidic devicesand computational modeling to better study vascularization dynamics in cancer [18].The harmonization of data coming from different fields [19,20] and the exchange of expertiseat several levels are fundamental parts of an essential strategy whose final aim is to accelerate thetranslation and the design of more precise preclinical models, in a true accomplishment of the “frombench to bedside” paradigm.Author Contributions: Both the authors wrote the manuscript. Both the authors have read and agreed to thepublished version of the manuscript.Acknowledgments: The authors thank Giulia Iaccarino and Debora Capece for fruitful discussion.Conflicts of Interest: The authors declare no conflict of interest.References1. Leggieri, A.; Attanasio, C.; Palladino, A.; Cellerino, A.; Lucini, C.; Paolucci, M.; Terzibasi Tozzini, E.;de Girolamo, P.; D’Angelo, L. Identification and Expression of Neurotrophin-6 in the Brain of Nothobranchiusfurzeri: One More Piece in Neurotrophin Research. J. Clin. Med. 2019, 8, 595. [CrossRef] [PubMed]2. Lossi, L.; Castagna, C.; Granato, A.; Merighi, A. The Reeler Mouse: A Translational Model of HumanNeurological Conditions, or Simply a Good Tool for Better Understanding Neurodevelopment? J. Clin. Med.2019, 8, 2088. [CrossRef] [PubMed]J. Clin. Med. 2020, 9, 1011 4 of 43. Montesano, A.; De Felice, E.; Leggieri, A.; Palladino, A.; Lucini, C.; Scocco, P.; de Girolamo, P.; Baumgart, M.;D’Angelo, L. 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Preclinical Models: Boosting Synergies for Improved Translation

Chiara Attanasio

Mara Sangiovanni

Multidisciplinary Digital Publishing Institute

https://www.iris.unina.it/bitstream/11588/802220/1/JCM%20Preclinical%20models%202020.pdf

Preclinical Models: Boosting Synergies for Improved Translation

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Archivio della ricerca - Università degli studi di Napoli Federico II

Multidisciplinary Digital Publishing Institute