Abstract

EditorialDeconstructing Organs: Single-Cell Analyses, Decellularized Organs, Organoids, and Organ-on-a-Chip ModelsAn American Physiological Society cross-journal Call for Papers on “Deconstructing Organs: Single-Cell Analyses, Decellularized Organs, Organoids, and Organ-on-a-Chip Models”Josephine C. Adams, P. Darwin Bell, Sue C. Bodine, Heddwen L. Brooks, Nigel Bunnett, Bina Joe, Kara Hansell Keehan, Thomas R. Kleyman, André Marette, Rory E. Morty, Jan-Marino Ramírez, Morten B. Thomsen, Bill J. Yates, and Irving H. ZuckerJosephine C. AdamsSchool of Biochemistry, Faculty of Life Sciences, University of Bristol, Bristol, United Kingdom, P. Darwin BellDivision of Nephrology, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, Sue C. BodineDivision of Endocrinology and Metabolism, Department of Internal Medicine, Carver College of Medicine, University of Iowa, Iowa City, Iowa, Heddwen L. BrooksDepartment of Physiology, University of Arizona College of Medicine, Tucson, Arizona, Nigel BunnettDepartment of Molecular Pathobiology, New York University, New York, New York, Bina JoeDepartment of Physiology and Pharmacology, University of Toledo College of Medicine and Life Sciences, Toledo, OhioCenter for Hypertension and Personalized Medicine, University of Toledo College of Medicine and Life Sciences, Toledo, Ohio, Kara Hansell KeehanAmerican Physiological Society, Rockville, Maryland, Thomas R. KleymanDepartment of Medicine, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Cell Biology, University of Pittsburgh, Pittsburgh, PennsylvaniaDepartment of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, Pennsylvania, André MaretteDepartment of Medicine, Faculty of Medicine, Cardiology Axis of the Québec Heart and Lung Institute, Hôpital Laval, Quebec City, Quebec, CanadaInstitute of Nutrition and Functional Foods, Laval University, Quebec City, Quebec, Canada, Rory E. MortyDepartment of Lung Development and Remodelling, Max Planck Institute for Heart and Lung Research, Bad Nauheim, GermanyDepartment of Internal Medicine (Pulmonology), University of Giessen and Marburg Lung Center, Justus Liebig University Giessen, member of the German Center for Lung Research (DZL), Giessen, Germany, Jan-Marino RamírezDepartment of Neurological Surgery, University of Washington Medical Center, Seattle, WashingtonCenter on Human Development and Disability, University of Washington, Seattle, WashingtonCenter for Integrative Brain Research, Seattle Children’s Research Institute, University of Washington, Seattle, Washington, Morten B. ThomsenDepartment of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark, Bill J. YatesDepartment of Otolaryngology, University of Pittsburgh, Pittsburgh, Pennsylvania, and Irving H. ZuckerDepartment of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, NebraskaPublished Online:28 Jul 2020https://doi.org/10.1152/ajplung.00311.2020This is the final version - click for previous versionMoreSectionsPDF (139 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations ShareShare onFacebookTwitterLinkedInWeChat INTRODUCTIONThe past three decades have seen tremendous advances in the development and application of new in vitro and ex vivo approaches to study cell, tissue, organ, and system function. The most recognizable of these today is single-cell analysis, which has its roots in the first amplification of cDNA from individual hematopoietic cells in 1990 (6), and the first analysis of gene expression in single neurons in 1992 (13). These studies laid foundations for the first transcriptomic analysis of a single cell—a mouse blastomere—by mRNA sequencing in 2009 (65), followed by the first single-cell DNA sequencing of human breast tumors (43). Single-cell RNA-seq in particular has allowed for gene expression to be studied at an unprecedented resolution (80), and single-cell approaches continue to be developed and refined—at rapid pace—for proteomic (34), epigenomic (51), metabolomic (20), and lipidomic (22) analyses. These single-cell approaches have led to a fuller appreciation of the complexity of cell diversity in a tissue, organ, or system, which is not possible with more traditional approaches where multicellular samples are subjected to “bulk” analyses (49).Methodological developments have not been restricted to single-cell analyses. Culturing populations of cells ex vivo remains a gold-standard method for mechanistic studies of molecular pathways. Indeed, “Making Cell Culture More Physiological” is an ongoing Call for Papers at the American Journal of Physiology-Cell Physiology, which seeks to advance the communication of research activities that enhance the physiological relevance of cell culture practices and technology, or in which physiologically relevant models are applied to new research questions (1). That Call for Papers is complemented by the new Call for Papers on “Deconstructing Organs,” introduced in this Editorial, which addresses integrated, organ-level structures. There is now increased appreciation for the utility of decellularized tissues (and indeed, entire organs) as platforms for in vitro modeling of healthy and disease tissues (37), which has extended to decellularized tissue serving as scaffolds for tissue and organ regeneration, and subsequent transplantation (14). Other technological developments include the partial reconstitution of cellular components of tissues and organs in in vitro systems (24), for example, organoids, which recapitulate elements of the cellular heterogeneity, structure, and functions of the primary tissue (10), and which are particularly powerful since components of the organoid can be predefined. Similar to organoids, organ-on-a-chip models allow for predefined compartmentalization of the cellular components of three-dimensional (3D) cell-cultures. These organ-on-a-chip models particularly lend themselves to studies on the vasculature (52) and inhalation (4), given the microfluidic component of the chip structure (38). While organoids and organ-on-a-chip models partially reconstitute tissue and organ structures, the original structure of the primary tissue is preserved in organotypic slice cultures (19), initially developed for studies on the mouse hippocampus in 1976 (71). With the advent of the vibrating microtome (27), precision-cut organotypic slice cultures can now be prepared from any tissue or organ, and can be used alone, or as substrata for the culture of dissociated cells (15); and have thus found widespread application in toxicology, physiology, and imaging studies (19).All of these in vitro methodological developments, which effectively deconstruct (and partially reconstruct) organs, have provided investigators with a wealth of new experimental approaches to study the behavior and interactions of the approximately 37 trillion cells that are estimated to constitute the human body (5). These approaches can, of course, be applied to the study of any cell, tissue, organ, or system of any species. To acknowledge the emerging importance of these in vitro technologies in studies on integrated normal and pathologic physiological processes, 10 journals that publish Research Articles and Innovative Methodology articles within the American Physiological Society’s publications portfolio have joined together to issue a cross-journal Call for Papers entitled “Deconstructing Organs: Single-Cell Analyses, Decellularized Organs, Organoids, and Organ-on-a-chip Models.”This Call for Papers aims to attract Research Articles that report studies on normal or pathologic physiological processes, which employ single-cell analyses, decellularized organs, organoids, organ-on-a-chip models, precision-cut organotypic slice cultures, or complex cell cultures. Manuscripts that report the development of new in vitro methods, or the refinement of existing in vitro methods, may also be submitted under the methodology category of manuscripts, either Methods in Cell Physiology (at the American Journal of Physiology-Cell Physiology) or Innovative Methodology (at all other participating journals, except Physiological Reports). Journal-specific information is provided below for each participating journal.Authors should submit to one participating journal that best fits the thematic focus of their report. Manuscripts will be peer reviewed and, if accepted, published in the participating journal to which the authors submitted. A cross-journal collection at https://journals.physiology.org will highlight all articles published in this Call for Papers across all of the participating journals. Editors of participating journals will consider both original research articles and review articles. For review articles only, authors should email the editorial office of the participating journal to which they wish to submit, with a presubmission inquiry including a working title, author and affiliation lists, abstract, and brief outline of the content for approval by the editors.AJP-CELL PHYSIOLOGYThe American Journal of Physiology-Cell Physiology solicits Research Articles, Methods in Cell Physiology articles, and Mini-Reviews in relation to its ongoing Call for Papers “Making Cell Culture More Physiological.” As outlined in Ref. 1, that Call for Papers is an initiative to support advancements in all areas of cell culture and is relevant to all cell types. Examples of research topics published to date include making appropriate choices of cells (58); physiologically appropriate culture conditions (81); the relevance of high-throughput models (74); 3D cell environments and scaffolds (48); organoids (10), and organs-on-chips. A related thematic collection of invited Reviews is under publication, and the current collection of these Reviews can be found at https://journals.physiology.org/topic/ajpcell-collections/make-cell-culture-more-physiological. Submission of articles related to application of organoids, organs-on-chips, or decellularized tissue materials are welcome under either the Call for Papers “Making Cell Culture more Physiological” or the complementary, new Call for Papers on “Deconstructing Organs.” Please submit via the online portal at https://ajpcell.msubmit.net. Authors interested in contributing a Review under either Call should please contact the Editor-in-Chief, Dr. Josephine Adams, at [email protected], to whom questions related to either Call for Papers can also be addressed.AJP-ENDOCRINOLOGY AND METABOLISMThe American Journal of Physiology-Endocrinology and Metabolism solicits manuscripts that report original, mechanistic studies that employ single-cell analyses, decellularized organs, and organoids from metabolic or endocrine tissues. Manuscripts that report organ-on-a-chip models, other complex coculture systems, or cell-based methods allowing the detection, measurement and/or visualization of complex cross talk mechanisms in endocrine and metabolic cells, as well as other forms of “deconstructed” organs will also be considered. The articles will complement the Journal’s existing Call for Papers “Immunometabolic Cross-Talk and Regulation of Endocrine and Metabolic Functions,” which addresses integrative organ cross-talk, paracrine, and autocrine mechanisms by which immune factors in metabolic organs can trigger inflammation through complex cell to cell communications, outlined at https://journals.physiology.org/ajpendo/Immunometabolic-Cross-Talk-and-Regulation-of-Endocrine-and-Metabolic-Functions. The Call for Papers in “Deconstructing Organs” described in this Editorial will also complement the Journal’s recent focus on how gut microbes communicate with host mammalian cells through specific host receptors involved in the control of energy metabolism by a gut-to-brain and gut-to-liver axes, thereby leading to dynamic interactions between microbes, dietary elements and organs. Please submit your manuscript to the American Journal of Physiology-Endocrinology & Metabolism via the eJournalPress portal at https://ajpendo.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. André Marette, at [email protected]AJP-GASTROINTESTINAL AND LIVER PHYSIOLOGYThe American Journal of Physiology-Gastrointestinal and Liver Physiology solicits Research Articles and Reviews concerning the use of tissue engineering, stem cells, and organ-on-a-chip models to study physiological and pathophysiological processes in the gastrointestinal tract, liver, and pancreas. The articles will complement the Journal’s recent Themed Issue on “The Engineered Gut: Use of Stem Cells and Tissue Engineering to Study Physiological Mechanisms and Disease Processes.” The current collection of these articles can be found at https://journals.physiology.org/topic/ajpgi-collections/the-engineered-gut. The Journal is keen to publish articles using a tissue-engineering approach to examine mechanistic details of physiological control, disease processes, and therapeutic interventions. Articles using tissue-engineering technologies to study microbiome-host interactions are particularly welcome, and will complement the Journal’s upcoming Themed Issue on “The New Microbiome.” Please submit your manuscript to the American Journal of Physiology-Gastrointestinal and Liver Physiology via the eJournalPress portal at https://ajpgi.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. Nigel Bunnett, at [email protected]AJP-HEART AND CIRCULATORY PHYSIOLOGYThe American Journal of Physiology-Heart and Circulatory Physiology is especially interested in Research Articles and Rapid Reports that relate to cardiac reconstruction using novel bioengineering and scaffolding techniques. Our Journal has previously published papers related to cardiac and vascular reconstruction (3, 18, 29, 59, 60) using state of the art bioengineering techniques. The submission of manuscripts that take this technology to a new level and that focus on mechanisms of normal and pathological function as well as therapeutic potential are particularly encouraged. Review Articles and Systematic Review Articles related to organ-on-a-chip, seeding of scaffolds, or other bioengineering techniques are especially welcome. The Editors encourage the submission of single-cell transcriptomic, proteomic, and metabolomic studies that shed light on mechanistic physiological processes. Submission of novel methodological (46) and validation papers is also encouraged (72). Please submit your manuscript to the American Journal of Physiology-Heart and Circulatory Physiology via the eJournalPress portal at https://ajpheart.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. Irving H. Zucker, at [email protected]AJP-LUNG CELLULAR AND MOLECULAR PHYSIOLOGYThe difficulty of maintaining isolated, ventilated, and perfused ex vivo lungs for protracted periods of time has generated much enthusiasm for other ex vivo or in vitro models of the lung, or of lung tissue (17). New ways to reconstitute the blood-gas barrier in vitro has received particular attention, primarily using organ-on-a-chip models (31), and our Journal has recently reported the use of organ-on-a-chip technology to study the contribution of mesenchymal cells to vessel formation during development (73). These ideas have been expanded to organoid studies, where our Journal has recently reported, for example, the use of organoids to study epithelial-mesenchymal interactions in obstructive and restrictive lung disease (45) and in aberrant lung development (63, 64). Decellularized lung scaffolds have proved to be a versatile new tools for studying lung repair and regeneration ex vivo (21), and recent reports in our Journal have highlighted the use of decellularized lung scaffolds to define distinct niches within the lung extracellular matrix (ECM) that define fibroblast function (8). Additionally, efforts to promote ex vivo vascularization of scaffolds (62), with the long-term aim of bioengineering lungs (53), has been reported, along with the identification of targeted interventions that drive cellular repopulation of decellularized scaffolds (70). Studies with lung scaffolds are frequently supported by work in precision-cut lung slices (33), for example, recent reports in our Journal where an ex vivo model of lung fibrosis was developed using precision-cut lung slices (2), and the where precision-cut lung slices were used to study airway smooth muscle photorelaxation (76). Moving on to single-cell studies, single-cell RNA-seq has emerged as a powerful tool to understand cell differentiation during lung development (75), and the perspective for single-cell analyses to advance our knowledge about lung development has been outlined in a recent Review in our Journal (32).If your manuscript reports the use of single cell analyses, decellularized organs, organoids, organ-on-a-chip models, as well as precision-cut lung slices and complex cell culture approaches to study any aspect of lung physiology or disease, or reports the methodological development of these technologies, submit your manuscript to the American Journal of Physiology-Lung Cellular and Molecular Physiology via the eJournalPress portal at https://ajplung.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. Rory E. Morty, at [email protected]AJP-RENAL PHYSIOLOGYThe American Journal of Physiology-Renal Physiology is interested in Research Articles that relate to the characterization of renal pluripotent stem/progenitor cells and organoids for the study of renal health and disease, the development of renal ECM scaffolds, and novel renal tissue engineering and regenerative medicine approaches for renal replacement therapies.Organoids differentiated from human pluripotent stem cells have been developed over recent years to study several kidney disorders (40, 41). A recently published article in our Journal reported a simple, cost-effective method to generate large numbers of organoids, suited for injury modeling and drug development (11). Thus, the submission of novel methodological and validation papers is encouraged. The isolation and propagation of primary cultures of many renal cell types has been problematic. Our Journal recently published an elegant study that utilized genetic tools to develop a new cell line that will allow the study of resident renal mesenchymal stem cell-like progenitors in renal fibrotic mechanisms (47). Three-dimensional in vitro models have also allowed new pathways to be identified in renal cyst development [reviewed in (12)]. The submission of manuscripts that combine new models/cell lines and that use single-cell transcriptomic, proteomic, and metabolomic studies to shed light on the cellular identification of renal progenitors, or that identify new mechanisms of normal or pathological renal function are highly encouraged. Review Articles related to novel renal tissue engineering and regenerative medicine approaches for renal replacement therapies are welcomed. The Editors encourage the submission of manuscripts to the American Journal of Physiology-Renal Physiology via the eJournalPress portal at https://ajprenal.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. Heddwen L. Brooks at [email protected]JOURNAL OF APPLIED PHYSIOLOGYThe Journal of Applied Physiology is especially interested in Research Articles that examine the use of engineered 3D organoids to study skeletal muscle and tendon physiology and pathophysiology in vitro. Our Journal is interested in the use of 3D organoids of skeletal muscle in the investigation of mechanisms underlying muscle atrophy and hypertrophy. In addition, we are interested in submissions that examine the functional properties of engineered tendons and their usefulness for the study of tendon injuries and repair.We encourage the submission of Research Articles and Reviews that examine the translational potential of 3D organoids of skeletal muscle and tendons, especially as related to their use in regenerative medicine and the testing of therapeutics. Submit your manuscript to the Journal of Applied Physiology via eJournalPress portal at https://jappl.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. Sue C. Bodine, at [email protected]JOURNAL OF NEUROPHYSIOLOGYGiven the brain’s complexity, the introduction of in vitro approaches has been particularly important for neuroscience. In vitro systems are amenable to rigorous experimental approaches that aim at unraveling the cellular as well as systems-level mechanisms underlying normal and pathological brain functions. These approaches enable investigators to isolate and characterize particular brain regions, and to study the connectivity between specific regions. Reduced systems can also permit high-throughput testing of different drugs or modulators (35, 50, 55), and the introduction of organoid technologies has created new opportunities for precision and personalized medicine (30, 68). However, every in vitro approach also comes with numerous caveats and it is critical for each of these approaches to evaluate to what extent a reductionist approach preserves the physiological functions of the whole organism (56). In vitro approaches can trigger decade-long controversies, in particular if reductionist approaches generate new concepts and unexpected findings. But, luckily, not only are in vitro approaches constantly improving (61, 67, 78), but there has also been considerable progress in the development of novel in vivo approaches (25, 42). Together, these technical advances have tremendously accelerated our understanding of neuroscience.In this Call for Papers on deconstructing organs, prospective contributors are invited to submit their manuscripts to the Journal of Neurophysiology. The Journal of Neurophysiology has a long tradition of publishing cutting-edge in vitro studies (9, 23, 26, 36, 39, 44, 57, 66). Thus, the submission of manuscripts that report the use of single-cell analyses, decellularized organs, organoids, organ on a-chip models to study any aspect of neurophysiology or disease are particularly encouraged, as are reports of methodological development of these technologies and their relevance for understanding brain functions. Submit manuscript to the Journal of Neurophysiology via the eJournalPress portal at https://jn.msubmit.net. Please address any questions related to this Call for Papers to the Editor-in-Chief, Dr. Jan-Marino Ramírez, at [email protected]PHYSIOLOGICAL GENOMICSSince the dawn of the era of modern biology in the mid-1980s with the advent of PCR, the explosion of the “omics era” in the 21st century has left an unprecedented footprint on the landscape of physiological research. Almost all, if not most of what physiologists study in recent times, whether it is the function of an organ system, organ, tissue, or cell, has elements that can be traced back to the fundamental molecule of life, DNA (28). Depending on the scale of the physiological question posed, experimental designs vary in breadth and scope from the products of a single gene or that of a whole genome.Determining the functional consequences of genomic variants suspected to cause disease is slow owing to the paucity of suitable designs to study cause-effect relationships. In this context, deconstructing organs in petri dishes to study their genomic signature is an interesting approach employed by physiologists. Our Journal has recently published one such article describing the functional genomic analysis of human colon organoids. By combining this organoid approach with genome-wide analysis of open chromatin by ATAC-Seq and transcriptome mapping, key transcription factors were identified (77). Similarly, the value of studying constructing stem cell microenvironments using bioengineering approaches such as for example, using single LGR5+ intestinal stem cells expanded into long-lived gastric organoids resembling mature pyloric epithelium to study stem cell function has also been described in an article in Physiological Genomics (7). Future trends in using organoids for ascertaining variant-function relationship as part of the future of genomic medicine are highlighted in a review article published in Physiological Genomics (54).Building on this, Physiological Genomics invites articles focused on the use of single-cell analyses, decellularized organs, organoids, organ-on-a-chip models to study any aspects of functional genomics of any complex trait or disease in any species including improvements in methodologies of these technologies as applicable to mining genomic data. In this context, the attention of prospective contributors is drawn to three unique calls for papers in Physiological Genomics alongside this Call for Papers, all of which are accessible at https://journals.physiology.org/Calls: (1) “Single-Cell Sequencing”; (2) “Single-Cell Sequencing Bioinformatics Platforms”; (3) “Precision Medicine and Complex Disease”. Submit your manuscript to Physiological Genomics at https://physiolgenomics.msubmit.net. Please address any questions related to these Calls for Papers to the Editor-in-Chief, Dr. Bina Joe, at [email protected]PHYSIOLOGICAL REPORTSPhysiological Reports publishes articles covering all areas of physiology. With this Call for Papers, authors are encouraged to submit original work to Physiological Reports focusing on single-cell analyses, decellularized organs, 3D printed organ scaffolds, organoids, and organ-on-a-chip models. The submission of Review Articles covering these topics is also encouraged. Physiological Reports has published several manuscripts using organoids or 3D culture models to address specific physiologic questions (16, 69, 79). Manuscripts reporting the use of human-derived induced pluripotent stem cells differentiated to specific cell types to address questions regarding both normal physiology and pathophysiology are particularly encouraged. Physiological Reports welcomes work that is primarily descriptive in nature rather than mechanistic, and publishes both negative and confirmatory findings. While Physiological Reports publishes manuscripts focused on novel physiologic methodologies, it does not have an Innovative Methodology manuscript category. Please submit your manuscript, which may be an Original Research article, a Case Report, a Review, or a Letter to the Editor, through the online portal at https://mc.manuscriptcentral.com/physiologicalreports. For any questions regarding this Call for Papers, please contact our Editor-in-Chief, Dr. Thomas Kleyman at [email protected], or our Deputy Editor-in-Chief, Dr. Morten Thomsen at [email protected]For submissions to all participating journals, during the submission process, under the “Keywords & Special Sections” tab, select the “Category” drop-down menu and select “Call for Papers: Deconstructing Organs: Single-Cell Analyses, Decellularized Organs, Organoids, and Organ-on-a-Chip Models.” The deadline for submissions is 31 December 2021.GRANTST.R.K. is supported by the National Institutes of Health through National Institute of Diabetes and Digestive and Kidney Diseases Grant U01 DK107350. R.E.M. is supported by the Max Planck Society (MPI-HLR), the German Center for Lung Research (Deutsches Zentrum für Lungenforschung; DZL) (DZL-UGMLC), and the German Research Foundation (Deutsche Forschungsgemeinschaft; DFG) through EXC2026 [390649896], SFB1213 [268555672], KFO309 [284237345], Mo1789/1-1 [160966624] and Mo1789/4-1 [420759458]. J.-M.R. is supported by the National Institutes of Health through National Heart, Lung, and Blood Institute Grants R01 HL151389, R01 HL126523, R01 HL144801, P01 HL090554.DISCLOSURESJ. C. Adams is the Editor-in-Chief of the American Journal of Physiology-Cell Physiology. P. D. Bell is the former Editor-in-Chief of the American Journal of Physiology-Renal Physiology. S. C. Bodine is the Editor-in-Chief of the Journal of Applied Physiology. H. L. Brooks is the Editor-in-Chief of the American Journal of Physiology-Renal Physiology. N. Bunnett is the Editor-in-Chief of the American Journal of Physiology-Gastrointestinal and Liver Physiology. B. Joe is the Editor-in-Chief of Physiological Genomics. K. H. Keehan is Executive Editor of the American Journal of Physiology-Heart and Circulatory Physiology and is an employee of the American Physiological Society. T. R. Kleyman is the Editor-in-Chief of Physiological Reports. A. Marette is the Editor-in-Chief of the American Journal of Physiology-Endocrinology and Metabolism. R. E. Morty is the Editor-in-Chief of the American Journal of Physiology-Lung Cellular and Molecular Physiology. J.-M. Ramírez is the Editor-in-Chief of the Journal of Neurophysiology. M. B. Thomsen if the Deputy Editor-in-Chief of Physiological Reports. B. J. Yates is the former Editor-in-Chief of the Journal of Neurophysiology. I. H. Zucker is the Editor-in-Chief of the American Journal of Physiology-Heart and Circulatory Physiology. All Editors are compensated by the American Physiological Society for their services.AUTHOR CONTRIBUTIONSJ.C.A., P.D.B., S.C.B., H.L.B., N.B., B.J., K.H.K., T.R.K., A.M., R.E.M., J.-M.R., M.B.T., B.J.Y., and I.H.Z. drafted manuscript; edited and revised manuscript; and approved final version of manuscript.REFERENCES1. Adams JC. A new initiative for AJP-Cell Physiology: “Making Cell Culture More Physiological”. Am J Physiol Cell Physiol 316: C828–C829, 2019. doi:10.1152/ajpcell.00157.2019. Link | ISI | Google Scholar2. Alsafadi HN, Staab-Weijnitz CA, Lehmann M, Lindner M, Peschel B, Königshoff M, Wagner DE. An ex vivo model to induce early fibrosis-like changes in human precision-cut lung slices. Am J Physiol Lu

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